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Council of the

European Union

Brussels, 2 June 2025

(OR. en)

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SAN 243
PHARM 71
MI 320
COMPET 410
ENV 386
PI 94
CODEC 664
IA 49
UK 94

Interinstitutional File:

2023/0132 (COD)

NOTE
From:

General Secretariat of the Council

To:

Permanent Representatives Committee

No. prev. doc.:

8539/25

Subject:

Proposal for a DIRECTIVE OF THE EUROPEAN PARLIAMENT AND OF
THE COUNCIL on the Union code relating to medicinal products for human
use, and repealing Directive 2001/83/EC and Directive 2009/35/EC
- Mandate for negotiations with the European Parliament

Delegations will find in Annex the revised text of the draft proposal for a Directive on the Union

code relating to medicinal products for human use, and repealing Directive 2001/83/EC and

Directive 2009/35/EC.

Changes compared to the Commission proposal are indicated in strikethrough for deletions and

bold/underline for new text made in document. In addition, changes compared to previous revised

texts are highlighted in grey.

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ANNEX

2023/0132 (COD)

Proposal for a

DIRECTIVE OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL

on the Union code relating to medicinal products for human use, and repealing Directive

2001/83/EC and Directive 2009/35/EC

(Text with EEA relevance)

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION,

Having regard to the Treaty on the Functioning of the European Union, and in particular Articles

114(1) and 168(4)(c) thereof,

Having regard to the proposal from the European Commission,

After transmission of the draft legislative act to the national parliaments,

Having regard to the opinion of the European Economic and Social Committee,

Having regard to the opinion of the Committee of the Regions,

Acting in accordance with the ordinary legislative procedure,

Whereas:

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(1) The Union general pharmaceutical legislation was established in 1965 with the dual objective

of safeguarding public health and harmonising the internal market for medicines. It has

developed considerably since then, but these overarching objectives have guided all revisions.

The legislation governs the granting of marketing authorisations for all medicines for human

use by defining conditions and procedures to enter and remain on the market. A fundamental

principle is that a marketing authorisation is granted only to medicines with a positive benefit-

risk balance after assessment of their quality, safety and efficacy.

(2) The most recent comprehensive revision took place between 2001 and 2004 while targeted

revisions on post-authorisation monitoring (pharmacovigilance) and on falsified medicines

were adopted subsequently. In the almost 20 years since the last comprehensive revision, the

pharmaceutical sector has changed and has become more globalised, both in terms of

development and manufacture. Moreover, science and technology have evolved at a rapid

pace. However, there continues to be unmet medical needs, i.e. diseases without or only with

suboptimal treatments. Moreover, some patients may not benefit from innovation because

medicines may be unaffordable or not placed on the market in the Member State concerned.

There is also a greater awareness of the environmental impact of medicines. More recently,

the COVID-19 pandemic has stress tested the framework.

(3) This revision is part of the implementation of the Pharmaceutical strategy for Europe and

aims to promote innovation, in particular for unmet medical needs, while reducing regulatory

burden and the environmental impact of medicines; ensure access to innovative and

established medicines for patients, with special attention to enhancing security of supply and

addressing risks of shortages, taking into account the challenges of the smaller markets of the

Union; and create a balanced and competitive system that keeps medicines affordable for

health systems while rewarding innovation.

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(4) This revision focuses on provisions relevant to achieve its specific objectives; therefore it

covers all but provisions concerning falsified medicines, homeopathic and traditional herbal

medicines. Nevertheless, for the sake of clarity, it is necessary to replace Directive

2001/83/EC of the European Parliament and of the Council1 with a new Directive. The

provisions on falsified medicines, homeopathic medicines and traditional herbal medicines are

therefore maintained in this Directive without changing their substance compared to previous

harmonisations. However, in view of the changes in the governance of the Agency, the Herbal

Committee is replaced by a working group.

(5) The essential aim of any rules governing the authorisation, manufacturing, supervision,

distribution and use of medicinal products must be to safeguard public health. Such rules

should also ensure the free movement of medicinal products and the elimination of obstacles

to trade in medicinal products to all patients in the Union.

(6) The regulatory framework for medicinal products use should also take into account the needs

of the undertakings in the pharmaceutical sector and trade in medicinal products within the

Union, without jeopardising the quality, safety and efficacy of medicinal products.

(7) The EU and all its Member States as parties to the United Nations Convention on the Rights

of Persons with Disabilities are bound by its provisions to the extent of their competences.

This includes the right to access information as set out in Article 21 and the right to the

enjoyment of the highest attainable standard of health without discrimination on the basis of

disability as set in Article 25.

Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the
Community code relating to medicinal products for human use (OJ L 311, 28.11.2001, p. 67).

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(8) This revision maintains the level of harmonisation that has been achieved. Where necessary

and appropriate, it further reduces the remaining disparities, by laying down rules on the

supervision and control of medicinal products and the rights and duties incumbent upon the

competent authorities of the Member States with a view to ensuring compliance with legal

requirements. In the light of experience gained on the application of the Union pharmaceutical

legislation and the evaluation of its functioning, the regulatory framework need to be adapted

to scientific and technological progress, the current market conditions and economic reality

within the Union. Scientific and technological developments induce innovation and

development of medicinal products, including for therapeutic areas where there is still unmet

medical need. To harness these developments, the Union pharmaceutical framework should

be adapted to meet scientific developments such as genomics, accommodate cutting edge

medicinal products, e.g. personalised medicinal products and technological transformation

such as data analytics, digital tools and the use of artificial intelligence. These adaptations

also contribute to competitiveness of the Union pharmaceutical industry.

(8a) Without affecting the rules laid down in this Directive, Member States remain the sole

responsible for their own national security. They are responsible in defending their

essential State functions, including ensuring their territorial integrity and safeguarding

national security. In particular, under Article 346 TFEU, no Member State is obliged to

supply information the disclosure of which it considers contrary to the essential interests

of its security. In particular, Member States should be enabled not to include under the

scope of this Directive medicinal products specifically manufactured and supplied

exclusively to the armed forces for matters of defence purposes, under the control of the

relevant national authorities.

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(9) Medicinal products for rare diseases and for children, should be subject to the same conditions

as any other medicinal product concerning their quality, safety and efficacy, for example for

what concerns the marketing authorisation procedures, quality and the pharmacovigilance

requirements. However, specific requirements also apply to them considering their unique

characteristics. Such requirements, which are currently defined in separate legislations, should

be integrated in general pharmaceutical legal framework in order to ensure clarity and

coherency of all the measures applicable to these medicinal products. Furthermore, as some

medicinal products authorised for use in children are authorised by the Member States,

specific provisions should be integrated in this Directive.

(10) The system of a directive and regulation for the general pharmaceutical legislation should be

maintained to avoid fragmentation of national legislation on medicinal products for human

use, given that the legislation is based on a system of national Member States and Union

marketing authorisations. Member States national marketing authorisations are granted and

managed on the basis of national law implementing the Union pharmaceutical law. The

evaluation of the general pharmaceutical legislation has not shown that the choice of legal

instrument has caused specific problems or created disharmonisation. In addition, a REFIT

Platform2 opinion in 2019 showed that there was not support among the Member States to

turn Directive 2001/83/EC into a Regulation.

(11) The Directive should work in synergy with the Regulation to enable innovation and promote

competitiveness of the Union pharmaceutical industry, in particular SMEs. In this respect a

balanced system of incentives is proposed that rewards innovation especially in areas of

unmet medical need and innovation that reaches patients and improves access across the

Union. To make the regulatory system more efficient and innovation-friendly the Directive

also aims at reducing administrative burden and simplifying procedures for undertakings.

The EU's efforts to simplify legislation – 2019 Annual Burden survey,
https://commission.europa.eu/system/files/2020-08/annual_burden_survey_2019_4_digital.pdf

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(12) The definitions and scope of Directive 2001/83/EC should be clarified in order to achieve

high standards for the quality, safety and efficacy of medicinal products and to address

potential regulatory gaps, without changing the overall scope, due to scientific and

technological developments, e.g. low-volume products, bedside-manufacturing or

personalised medicinal products that do not involve an industrial manufacturing process.

(13) To avoid the duplication of requirements for medicinal products in this Directive and in the

Regulation, the general standards in regards to quality, safety and efficacy of medicinal

products laid down in this Directive shall be applicable to medicinal products covered by

national marketing authorisation and also to medicinal products covered by centralised

marketing authorisation. Therefore, the requirements for an application for medicinal product

are valid for both, also the rules on prescription status, product information, regulatory

protection and rules on manufacturing, supply, advertising, supervision and other national

requirements shall be applicable to medicinal products covered by centralised marketing

authorisation.

(14) The determination of whether a product falls within the definition of a medicinal product must

be made on a case-by-case basis taking into account the factors set out in this Directive, such

as the product’s presentation or pharmacological, immunological or metabolic properties.

(15) In order to take account both of the emergence of new therapies and of the growing number of

so-called ‘borderline’ products between the medicinal product sector and other sectors, certain

definitions and derogations should be modified, so as to avoid any doubt as to the applicable

legislation. With the same objective of clarifying situations when a product fully falls within

the definition of a medicinal product and also meet the definition of other regulated products,

the rules for medicinal products under this Directive apply. Furthermore, to ensure the clarity

of applicable rules, it is also appropriate to improve the consistency of the terminology of the

pharmaceutical legislation and clearly indicate the products excluded from the scope of this

Directive.

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(16) The new definition for a substance of human origin (SOHO) by the SoHO Regulation (EU)

2024/1938 of the European Parliament and the Council3 covers any substance collected

from the human body in whatever manner, whether it contains cells or not and regardless of

whether it meets the definition of ‘blood’, ‘tissue’ or ‘cell’, for example human breast milk,

intestinal microbiota and any other SoHO that may be applied to humans in the future. Such

substances of human origin, other than tissues and cells, may become SoHO derived

medicinal products, other than ATMPs, when the SoHO is subject to an industrial process

involving systematisation, reproducibility and operations performed on a routine basis or

batch-wise resulting in a product of standardised consistency. When a process concerns

extraction of an active ingredient from the SoHO, other than tissues and cells, or a

transformation of a SoHO, other than tissues and cells, by changing its inherent properties,

this should also be considered a SoHO derived medicinal product. When a process concerns

concentrating, separating or isolating elements in the preparation of blood components, this

should not be considered as changing their inherent properties..

(17) For avoidance of doubt, the safety and quality of human organs intended for transplantation

are regulated only by Directive 2010/53/EU of the European Parliament and of the Council4,

and the safety and quality of substances of human origin intended for medically assisted

reproduction are regulated only by [SoHO Regulation or if not in force, Directive

2004/23/EC.

Regulation (EU) 2024/1938 of the European Parliament and of the Council of 13 June 2024 on
standards of quality and safety for substances of human origin intended for human application
and repealing Directives 2002/98/EC and 2004/23/EC (OJ L 1938, 17.07.2024, p. 1)

Directive 2010/45/EU of the European Parliament and of the Council of 7 July 2010 on standards of
quality and safety of human organs intended for transplantation (OJ L 207, 6.8.2010, p. 14).

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(18) Advanced therapy medicinal products that are prepared on a non-routine basis according to

specific quality standards, and then used within the same Member State in a hospital under

the exclusive professional responsibility of a medical practitioner, in order to comply with an

individual medical prescription for a custom-made product for an individual patient, should be

subject to a general exemption, while applying the specific rules excluded from the scope

of this Directive whilst at the same time ensuring that relevant Union rules related to quality

and safety are not undermined (‘hospital exemption’). Experience has shown that there are

great differences in the application of hospital exemption among Member States. To improve

the application of hospital exemption this Directive introduces measures for collection,

reporting of data as well as review of these data yearly by the competent authorities and their

publication by the Agency in a repository. Furthermore, the Agency should provide a report

on the implementation of hospital exemption on the basis of contributions from Member

States in order to examine whether an adapted framework should be established for certain

less complex ATMPs that have been developed and used under the hospital exemption. When

an authorisation approval for the manufacturing and use of an ATMP under hospital

exemption is revoked because of safety concerns, the relevant competent authorities shall

inform the competent authorities of other Member States, through the Agency.

(18a) In accordance with scientific knowledge, haptens, when combined with an endogenous

carrier substance, are allergens and should be construed as such for the purpose of

pharmaceutical legislation.

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(19) This Directive should be without prejudice to the provisions of Council Directive

2013/59/Euratom5, including with respect to justification and optimisation of protection of

patients and other individuals subject to medical exposure to ionising radiation. In the case of

radiopharmaceuticals used for therapy, marketing authorisations, posology and administration

rules have to notably respect that Directive’s requirements that exposures of target volumes

are to be individually planned, and their delivery appropriately verified taking into account

that doses to non-target volumes and tissues are to be as low as reasonably achievable and

consistent with the intended therapeutic purpose of the exposure.

(20) In the interest of public health, a medicinal product should only be allowed to be placed on

the market in the Union when the marketing authorisation has been granted to the medicinal

product, and its quality, safety and efficacy have been demonstrated. However, exemption

should be provided from this requirement in situations characterised by an urgent need to

administer a medicinal product to address the specific needs of a patient, or confirmed spread

of pathogenic agents, toxins, chemical agents or nuclear radiation that could cause harm. In

particular, to fulfil special needs, Member States should be allowed to exclude from the

provisions of this Directive medicinal products supplied in response to a bona fide unsolicited

order or anticipated bonafide unsolicited order, formulated in accordance with the

specifications of an authorised healthcare professional and for use by anto fullfill the needs

of individual patients under their direct personal responsibility. Member States should be also

allowed to temporarily authorise the distribution of an unauthorised medicinal product in

response to a suspected or confirmed spread of pathogenic agents, toxins, chemical agents or

nuclear radiation any of which could cause harm.

Council Directive 2013/59/Euratom of 5 December 2013 laying down basic safety standards for
protection against the dangers arising from exposure to ionising radiation, and repealing Directives
89/618/Euratom, 90/641/Euratom, 96/29/Euratom, 97/43/Euratom and 2003/122/Euratom (OJ L 13,
17.1.2014, p. 1).

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(20a) Pharmacies play a crucial role in providing medicinal products to patients. They may

prepare specific formulations, known as magistral formulas, tailored to individual needs

of patients based on the instructions of a doctor or of another healthcare professional

qualified to do so. In certain situations, it may be necessary to prepare these

formulations in advance. Additionally, pharmacies are responsible for creating standard

pharmaceutical preparations, referred to as officinal formulas. These are made

according to established guidelines found in pharmacopeias. Officinal formulas are

designed for general use and adhere to standardised recipes that are set by authoritative

pharmaceutical bodies. Unlike magistral formulas, they are not customised for

individual patients. Generally, these preparations are exempt from authorisation

requirements outlined in this Directive, though they may still be subject to national

regulations.

(20b) In exceptional cases, the Directive allows Member States to exclude medicinal products

from the scope to fulfil special needs of individual patients. In addition, to effectively

mitigate shortages, it is important to address the patients’ needs on population level and

allow the preparation of medicinal products, under strict conditions. Such exceptions

should never be aimed at distorting competition and should be interpreted narrowly,

and only used to mitigate or resolve a shortage or in a situation where there is no

relevant authorised product available on the market.

(21) Marketing authorisation decisions should be taken on the basis of the objective scientific

criteria of quality, safety and efficacy of the medicinal product concerned, to the exclusion of

economic or any other considerations. However, Member States should be able exceptionally

to prohibit the use in their territory of medicinal products.

(22) The particulars and documentations that are to accompany an application for marketing

authorisation for a medicinal product demonstrate that the therapeutic efficacy of the product

overweight potential risks. The benefit-risk balance of all medicinal products will be assessed

when they are placed on the market, and at any other time the competent authority deems

appropriate.

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(23) As market forces alone have proven insufficient to stimulate adequate research into, and the

development and authorisation of, medicinal products for the paediatric population, a system

of both obligations and rewards and incentives has been put in place.

(24) It is therefore necessary to introduce a requirement for new medicinal products or when

developing paediatric indications of already authorised products covered by a patent or a

supplementary protection certificate to present either the results of studies in the paediatric

population in accordance with an agreed paediatric investigation plan or proof of having

obtained a waiver or deferral, at the time of filing a marketing authorisation application or an

application for a new therapeutic indication, new pharmaceutical form or new route of

administration.

However, in order to avoid exposing patients, especially children, to unnecessary clinical

trials or due to the nature of the medicinal products, that requirement should not apply to

generics or similar biological medicinal products and medicinal products authorised through

the well-established medicinal use procedure, nor to homeopathic medicinal products and

traditional herbal medicinal products authorised through the simplified registration procedures

of this Directive.

(25) In order to ensure that the data supporting the marketing authorisation concerning the use of a

product in children to be authorised under this regulation have been correctly developed, the

competent authorities should check compliance with the agreed paediatric investigation plan

and any waivers and deferrals at the validation step for marketing authorisation applications.

(26) In order to reward the compliance with all the measures included in the agreed paediatric

investigation plan, for products covered by a supplementary protection certificate, if relevant

information on the results of the studies conducted is included in the product information, a

reward should be granted in the form of a six month extension of the supplementary

protection certificate created by [Regulation (EC) No 469/2009 of the European Parliament

and of the Council6- OP please replace reference by new instrument when adopted].

Regulation (EC) No 469/2009 of the European Parliament and of the Council of 6 May 2009
concerning the supplementary protection certificate for medicinal products (OJ L 152, 16.6.2009, p.
10).

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(27) Certain particulars and documentation that are normally to be submitted with an application

for a marketing authorisation should not be required if a medicinal product is a generic

medicinal product or a similar biological medicinal product (biosimilar) that is authorised or

has been authorised in the Union. Both generic and biosimilar medicinal products are

important to ensure access of medicinal products to a wider patient population and create a

competitive internal market. In a joint statement authorities of the Member States confirmed

that the experience with approved biosimilar medicinal products over the past 15 years has

shown that in terms of efficacy, safety and immunogenicity they are comparable to their

reference medicinal product and are therefore interchangeable and can be used instead of its

reference product (or vice versa) or replaced by another biosimilar of the same reference

product.

(28) Experience has shown that it is advisable to stipulate precisely the cases in which the results

of toxicological and pharmacological tests or clinical studies do not have to be provided with

a view to obtaining authorisation for a medicinal product that is essentially similar to an

authorised product, while ensuring that innovative undertakings are not placed at a

disadvantage. For these specified categories of medicinal products an abridged procedure

allows applicants to rely on data submitted by previous applicants and therefore to submit

only some specific documentation.

(29) For generic medicinal products only the equivalence of the generic medicinal product with the

reference medicinal product has to be demonstrated. For biological medicinal products, only

the results of comparability tests and studies are provided to the competent authorities. For

hybrid and bio-hybrid medicinal products i.e. in cases where the medicinal product does not

fall within the definition of a generic or biosimilar medicinal product or has changes in

strength, pharmaceutical form, route of administration or therapeutic indications, compared to

the reference medicinal product, the results of the appropriate non-clinical tests or clinical

studies shall be provided to the extent necessary to establish a scientific bridge to the data

relied upon in the marketing authorisation for the reference medicinal product.

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The same applies to bio-hybrids i.e. in cases where a biosimilar medicinal product has

changes in strength, pharmaceutical form, route of administration or therapeutic indications,

compared to the reference biological medicinal product. In the latter two situations, the

scientific bridge establishes that the active substance of the hybrid does not differ significantly

in properties with regard to safety or efficacy. Where it differs significantly in respect of those

properties, the applicant needs to submit a full application.

(30) Regulatory decision-making on the development, authorisation and supervision of medicines

may be supported by access and analysis of health data, including real world data i.e. health

data generated outside of clinical studies, where appropriate. The competent authorities

should be able to use such data, including via the European Health Data Space interoperable

infrastructure.

(31) Directive 2010/63/EU of the European Parliament and of the Council7 lays down provisions

on the protection of animals used for scientific purposes based on the principles of

replacement, reduction and refinement. Any study involving the use of animals, which

provides essential information on the quality, safety and efficacy of a medicinal product,

should take into account those principles of replacement, reduction and refinement, where

they concern the care and use of live animals for scientific purposes, and should be optimised

in order to provide the most satisfactory results whilst using the minimum number of animals.

The procedures of such testing should be designed to avoid causing pain, suffering, distress or

lasting harm to animals and should follow the available EMA and ICH guidelines. In

particular, the marketing authorisation applicant and the marketing authorisation holder

should take into account the principles laid down in Directive 2010/63/EU, including, where

possible, use new approach methodologies in place of animal testing. These can include but

are not limited to: in vitro models, such as microphysiological systems including organ-on-

chips, (2D and 3D-) cell culture models, organoids and human stem cells-based models; in

silico tools or read-across models.

Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the
protection of animals used for scientific purposes (OJ L 276, 20.10.2010, p. 33).

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(32) Procedures should be in place to facilitate joint animal testing, wherever possible, in order to

avoid unnecessary duplication of testing using live animals covered by Directive 2010/63/EU.

Marketing authorisation applicants and marketing authorisation holders should make all

efforts to reuse animal study results and make the results obtained from animal studies

publicly available. For abridged applications marketing authorisation applicants should refer

to the relevant studies conducted for the reference medicinal product.

(33) With respect to clinical trials, in particular those conducted outside the Union, on medicinal

products destined to be authorised within the Union, it should be verified, at the time of the

evaluation of the marketing authorisation application, that these trials were conducted in

accordance with the principles of good clinical practice and the ethical requirements

equivalent to the provisions of Regulation (EU) 536/2014 of the European Parliament and of

the Council8.

(34) There is the possibility under certain circumstances for marketing authorisations to be

granted, subject to specific obligations or conditions, on a conditional basis or under

exceptional circumstances. The legislation should allow under similar circumstances for

medicinal products with a standard marketing authorisation for new therapeutic indications to

be authorised on a conditional basis or under exceptional circumstances. The products

authorised on a conditional basis or under exceptional circumstances should in principle

satisfy the requirements for a standard marketing authorisation with the exception of the

specific derogations or conditions outlined in the relevant conditional or exceptional

marketing authorisation and shall be subject to specific review of the fulfilment of the

imposed specific conditions or obligations. The grounds for refusal of a marketing

authorisation should apply mutatis mutandis for such cases.

Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on
clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (OJ L 158,
27.5.2014, p. 1).

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(35) With the exception of those medicinal products that are subject to the centralised authorisation

procedure established by [revised Regulation (EU) No. 726/2004], a marketing authorisation

for a medicinal product should be granted by a competent authority in one Member State. In

order to avoid unnecessary administrative and financial burdens for applicants and competent

authorities, a full in-depth assessment of an application for the authorisation of a medicinal

product should be carried out only once. It is appropriate therefore to lay down special

procedures for the mutual recognition of national authorisations. Moreover, it should be

possible to submit through decentralised procedure the same application in parallel in

several Member States for the purpose of a common assessment under the lead of one of the

Member States concerned.

(36) Moreover, rules should be established under those procedures to resolve any disagreements

between competent authorities in a coordination group for mutual recognition and

decentralised procedures medicinal products (‘the coordination group’) without undue delay.

In the event of a disagreement between Member States about the quality, the safety or the

efficacy of a medicinal product, a scientific evaluation of the matter should be undertaken

according to a Union standard, leading to a single decision on the area of disagreement

binding on the Member States concerned. Whereas this decision should be adopted by a rapid

procedure ensuring close cooperation between the Commission and the Member States.

(37) In certain cases of major disagreement that cannot be solved, the case should be escalated and

be subject to a scientific opinion of the Agency, which is then implemented through a

Commission Decision.

(38) In order to better protect public health and avoid any unnecessary duplication of effort during

the examination of application for a marketing authorisation for medicinal products, Member

States should systematically prepare assessment reports in respect of each medicinal product

that is authorised by them, and exchange the reports upon request. Furthermore, a Member

State should be able to suspend the examination of an application for authorisation to place a

medicinal product on the market that is currently under active consideration in another

Member State with a view to recognising the decision reached by the latter Member State.

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(39) In the interest of as broad as possible access to medicinal products, a Member State that has

an interest in receiving access to a particular medicinal product undergoing authorisation

through the decentralised and mutual recognition procedures should be able to opt-into that

procedure.

(40) In order to increase availability of medicinal products, in particular on smaller markets, it

should, in cases where an applicant does not apply for an authorisation for a medicinal

product in the context of the mutual-recognition procedure in a given Member State, be

possible for that Member State, for justified public health reasons, to authorise the placing on

the market of the medicinal product.

(41) In the case of generic medicinal products of which the reference medicinal product has been

granted a marketing authorisation under the centralised procedure, applicants seeking

marketing authorisation should be able to choose either of the two procedures, on certain

conditions. Similarly, the mutual-recognition or decentralised procedure should remain

available as an option for certain medicinal products, even if they represent a therapeutic

innovation or are of benefit to society or to patients. Since generic medicines account for a

major part of the market in medicinal products, their access to the Union market should be

facilitated in the light of the experience acquired, therefore, the procedures to include other

Member States concerned to such procedure should be further simplified.

(42) The simplification of procedures should not have an impact on standards or the quality of

scientific evaluation of medicinal products to guarantee the quality, safety and efficacy and

therefore, the scientific evaluation period should remain. However, the reduction of overall

period for marketing authorisation procedure from 210 days to 180 days is foreseen.

(43) Member States should ensure adequate funding of competent authorities to carry out their

tasks under this Directive and [revised Regulation (EU) 726/2004]. In addition, Member

States should ensure adequate resources are assigned by the competent authorities for the

purpose of their contributions to the work of the Agency, taking into account the cost-based

remuneration they receive from the Agency.

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(44) As regards access to medicinal products, previous amendments to the Union pharmaceutical

legislation have addressed this issue by providing for accelerated assessment of marketing

authorisation applications or by allowing conditional marketing authorisation for medicinal

products for unmet medical need. While these measures accelerated the authorisation of

innovative and promising therapies, these medicinal products do not always reach the patient

and patients in the Union still have different levels of access to medicinal products. Patient

access to medicinal products depends on many factors. Marketing authorisation holders are

not obliged to market a medicinal product in all Member States; they may decide not to

market their medicinal products in, or withdraw them from, one or more Member States.

National pricing and reimbursement policies, the size of the population, the organisation of

health systems and national administrative procedures are other factors influencing market

launch and patient access.

(45) Addressing unequal patient access and affordability of medicinal products has become a key

priority of the Pharmaceutical Strategy for Europe, as also highlighted by Council

conclusions9 and a resolution of the European Parliament10. Member States called for revised

mechanisms and incentives for development of medicinal products tailored to the level of

unmet medical need, while ensuring health system sustainability, patient access and

availability of affordable medicinal products in all Member States.

(46) Access also comprise affordability. In this regard, the Union pharmaceutical legislation

respects the competence of the Member States in terms of pricing and reimbursement. In a

complementary manner, it aims to have a positive impact on affordability and sustainability of

health systems with measures that support competition from generic and biosimilar medicinal

products. The competition from generic and biosimilar medicinal products should also, in

turn, increase patient access to medicinal products.

Council conclusions on strengthening the balance in the pharmaceutical systems in the EU and its
Member States, (OJ C, C/269, 23.07.2016, p. 31). Council Conclusions on Access to medicines and
medical devices for a Stronger and Resilient EU, (2021/C 269 I/02).

European Parliament resolution of 2 March 2017 on EU options for improving access to medicine
(2016/2057(INI)) Shortages of medicines, 2020/2071(INI).

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(47) To ensure dialogue among all actors in the medicines lifecycle, discussions on policy issues

related to the application of the rules related to prolongation of regulatory data protection for

market launch availability of medicinal products shall take place in the Pharmaceutical

Committee. The Commission may invite bodies responsible for health technology assessment

as referred to in Regulation (EU) 2021/2282 or national bodies responsible for pricing and

reimbursement, as required, to participate in the deliberations of the Pharmaceutical

Committee.

(48) While pricing and reimbursement decisions are a Member State competence, the

Pharmaceutical Strategy for Europe announced actions to support cooperation of Member

States to improve affordability. The Commission has transformed the group of National

Competent Authorities on Pricing and Reimbursement and public healthcare payers (NCAPR)

from an ad-hoc forum to a continuous voluntary cooperation with the aim to exchange

information and best practices on pricing, payment and procurement policies to improve the

affordability and cost-effectiveness of medicines and health system’s sustainability. The

Commission is committed to stepping up this cooperation and further supporting information

exchange among national authorities, including on public procurement of medicines, while

fully respecting the competences of Member States in this area. The Commission may also

invite NCAPR members to participate in deliberations of the Pharmaceutical Committee on

topics that may have an impact on pricing or reimbursement policies, such as the market

launch incentive.

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(49) Joint procurement, whether within a country or across countries, can improve access,

affordability, and security of supply of medicines, in particular for smaller countries. Member

States interested in joint procurement of medicines can make use of Directive 2014/24/EU11,

which sets out purchasing procedures for public buyers, the Joint Procurement Agreement12

and the proposed revised Financial Regulation13. Upon request from the Member States the

Commission may support interested Member States by facilitating coordination to enable

access to medicines for patients in the Union as well as information exchange, in particular

for medicines for rare and chronic diseases.

(50) The establishment of a criteria-based definition of ‘unmet medical need’ is required to

incentivise the development of medicinal products in therapeutic areas that are currently

underserved. To ensure that the concept of unmet medical need reflects scientific and

technological developments and current knowledge in underserved diseases, the Commission

Agency should, in the form of scientific guidelines, specify and update using implementing

acts, the criteria specify the conditions concerning clinically relevant improvement in

efficacy, or in safety with at least comparable efficacy, in comparison with existing

medicinal products or other methods of diagnosis, prevention or treatment authorised in

the Union of satisfactory method of diagnosis, prevention or treatment, ‘remaining high

morbidity or mortality’, ‘relevant patient population’ following scientific assessment by the

Agency. The Agency will should seek input from a broad range of authorities or bodies active

along the lifecycle of medicinal products in the framework of the consultation process

established under the [revised Regulation (EC) No 726/2004] and also take into account

scientific initiatives at EU level or between Member States related to analysing unmet medical

needs, burden of disease and priority setting for research and development. The criteria for

‘unmet medical need’ can be subsequently used by Member States to identify specific

therapeutic areas of interest.

Directive 2014/24/EU of the European Parliament and of the Council of 26 February 2014 on public
procurement and repealing Directive 2004/18/EC (OJ L 94, 28.3.2014, p. 65).

Regulation (EU) 2022/2371 of the European Parliament and of the Council of 23 November 2022 on
serious cross-border threats to health and repealing Decision No 1082/2013/EU.

COM/2022/223 final.

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(51) The inclusion of new therapeutic indications to an authorised medicinal products contributes

to the access of patients to additional therapies and therefore should be incentivised.

(52) For the initial marketing authorisation application for medicinal products containing a new

active substance, the submission of clinical trials that include as a comparator an evidence-

based existing treatment should be incentivised, in order to foster the generation of

comparative clinical evidence that is relevant and can accordingly support subsequent health

technology assessments and decisions on pricing and reimbursement by Member States.

(53) A marketing authorisation holder should, within the limits of its responsibility, ensure the

appropriate stock levels and continuous supply of a medicinal product throughout its lifetime

to wholesale distributors, pharmacies or persons authorised to supply medicinal

products so that the needs of patients in the Member State in question are met

irrespective of whether that medicinal product is covered by a supply incentive or not.

Member States may specify the obligation in national law to the effect that sufficient

supplies to wholesalers are necessary to ensure an adequate supply to the patients in the

Member State in question.

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(53a) Access to medicinal products in all Member States and guaranteeing a timely, stable,

reliable and high-quality supply of medicinal products is an essential objective to

achieve an overall high level protection of human health in the Member States, thus

contributing to the protection of human health and human life in the Union. The

responsibility of ensuring a timely, adequate and continuous supply of medicinal

products so that to ensure that the needs of patients in a Member State are covered

rests, mainly, on the marketing authorisation holder. In principle, when a marketing

authorisation is granted, the medicinal product is placed on the market by the

marketing authorisation holder on its own initiative. Practice shows, however, that in

certain Member States the placing on the market of authorised medicinal products

does not occur or is delayed or occurs in quantities that do not correspond to the needs

of those Member States. Therefore, Member States should, based on grounds of public

health protection with due regard to the principle of proportionality and in compliance

with Union law, in particular concerning the free movement of goods and competition,

be enabled to require to the MAHs specific actions with a view to comply with their

market launch and supply obligations pursuant to this Directive and [revised

Regulation 726/2004/EC]. To this aim, Member States should be able to request the

marketing authorisation holder to submit an application for pricing and

reimbursement or to participate in any relevant national procurement procedures or

draw up and implement a roll-out plan that is acceptable for that Member State. The

implementation of the roll-out plan should ensure sufficient and continuous supply to

meet the needs of the patients in that Member State.

(54) Micro, small and medium-sized enterprises (‘SMEs’), not-for-profit entities or entities with

limited experience in the Union system should benefit from additional time to market a

medicinal product in the Member States where the marketing authorisation is valid for the

purposes of receiving additional regulatory data protection.

(55) When applying the provisions on market launch incentives, marketing authorisation holders

and Member States should do their utmost to achieve a mutually agreed supply of medicinal

products in accordance with the needs of the Member State concerned, without unduly

delaying or hindering the other party from enjoying its rights under this Directive.

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(56) Member States have the possibility to waive the condition of launch in their territory for the

purpose of the prolongation of data protection for market launch. This can be done through a

statement of non-objection to prolong the period of regulatory data protection. This is

expected to be the case particularly in situations where launch in a particular Member State is

materially impossible or because there are special reasons why a Member State wishes that

launch take place later.

(57) The issuing of documentation from the Member States as regards the prolongation of data

protection for the purpose of supply of medicinal products in all Member States where a

marketing authorisation is valid, in particular the waiver to the conditions for such

prolongation, does not affect at any time the powers of the Member States as regards the

supply, setting of prices for medicinal products or their inclusion in the scope of national

health insurance schemes. Member States do not waive the possibility to request release or

supply of the product concerned at any time before, during or after the prolongation of the

data protection period.

(58) An alternative way of demonstrating supply relates to the inclusion of medicinal products in a

positive list of medicinal products covered by the national health insurance system in

accordance with Directive 89/105/EEC. The related negotiations between companies and the

Member State should be conducted in good faith.

(59) A Member State that considers that the conditions of supply have not been met for its territory

should provide a reasoned statement of non-compliance at the latest in the Standing

Committee on Medicinal Products for Human Use procedure of the variation linked to the

provision of the relevant incentive.

(60) The Commission and Member States shall continuously monitor any data and learnings from

the application of the incentives system in order to improve, including through implementing

acts, how these provisions are applied. The Commission shall establish a list of national

contact points in this regard.

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(61) When a compulsory licence has been granted by a relevant authority in the Union to tackle a

public health emergency, regulatory data protection may, if still in force, prevent the effective

use of the compulsory licence as they impede the authorisation of generic medicinal products,

and thus access to the medicinal products needed to address the crisis. For this reason, data

and market protection should be suspended when a compulsory licence has been issued to

tackle a public health emergency. Such a suspension of the regulatory data protection should

be allowed only in relation to the compulsory licence granted and its beneficiary. The

suspension shall comply with the objective, the territorial scope, the duration and the subject

matter of the granted compulsory licence.

(62) The suspension of the regulatory data protection should be granted only for the duration of the

compulsory licence. A ‘suspension‘ of data and market protection in cases of public health

emergency shall mean that data and market protection shall produce no effect in relation to

the particular licensee of the compulsory licence while that compulsory licence is in effect.

When the compulsory licence ends, the data and market protection shall resume their effect.

The suspension should not result in an extension of the original duration.

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(63) It is currently possible for applicants for marketing authorisation of generic, biosimilar, hybrid

and bio-hybrid medicinal products to conduct studies, trials and the subsequent practical

requirements necessary to obtain regulatory approvals for those medicinal products during the

term of protection of the patent or Supplementary Protection Certificate (SPC) of the

reference medicinal product, without this being considered patent or SPC infringement. The

application of this limited exemption is however fragmented across the Union and it is

considered necessary, in order to facilitate the market entry of generic, biosimilar, hybrid and

bio-hybrid medicinal products that rely on a reference medicinal product, to clarify its scope

in order to ensure a harmonised application in all Member States, both in terms of

beneficiaries and in terms of activities covered. The exemption must be confined to conduct

the necessary studies, and trials and other activities needed for the regulatory approval

obtaining a marketing authorisation process, conducting health technology assessment and

obtaining pricing and reimbursement request approvals as well as submitting an

application on procurement tenders, where possible, even though this these may require

substantial amounts of test production to demonstrate reliable manufacturing. During the term

of protection of the patent or SPC of the reference medicinal product, there can be no

commercial use of the resulting final medicinal products obtained for the purposes of the

regulatory approval process, including the sale and offering for sale of such products, even

also with regards to procurement tenders.

(64) It The exemption will allow, inter alia, to conduct studies to support pricing and

reimbursement as well as the manufacture or purchase of patent protected active substances

for the purpose of seeking marketing authorisations during that period, thus contributing to

the market entry of generics and biosimilars on day one of loss of the patent or SPC

protection.

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(65) The competent authorities should refuse the validation for an application for a marketing

authorisation referring to data of a reference medicinal product only on the basis of the

grounds set out in this Directive. The same applies to any decision to grant, vary, suspend,

restrict or revoke the marketing authorisation. The competent authorities cannot base their

decision on any other grounds. In particular, those decisions cannot be based on the patent or

SPC status of the reference medicinal product. From these rules it also stems that the

protection of intellectual property rights does not represent a valid ground to refuse or

suspend decisions related to relevant pricing and reimbursement, health technology

assessment procedures, or where applicable, application for procurement tenders.

Member States remain free to introduce rules to ensure the readiness to supply a

medicinal product on the market of that Member State for the period when the patent

and SPC have expired.

(66) In order to address the challenge of antimicrobial resistance, where the pack is intended for

direct dispensing to patient, antimicrobials should be packaged in quantities that are

appropriate for the therapy cycle relevant for that product and national rules on antimicrobial

subject to prescription ensure that they are dispensed in a way that corresponds to the

quantities described by the prescription.

(67) The provision of information to healthcare professionals and to patients on the appropriate

use, storage and disposal of antimicrobials is a joint responsibility of marketing authorisation

holders and of Member States who should ensure appropriate collection system for all

medicinal products.

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(68) While this Directive restricts the use of antimicrobials by setting certain categories of

antimicrobials under prescription status, due to the growing antimicrobial resistance in the

Union, competent authorities of the Member States should consider further measures for

example expanding the prescription status of antimicrobials or the mandatory use of

diagnostic tests before prescription. Competent authorities of the Member States should

consider such further measures according to the level of antimicrobial resistance in their

territory and the needs of patients. The possibility of Member States to waive the

mandatory prescription-only status of antimicrobials, for example in case of specific low

dose formulations, should be strictly limited and well-justified based on public health

reasons.

(69) The pollution of waters and soils with pharmaceutical residues is an emerging environmental

problem, and there is scientific evidence that the presence of those substances in the

environment from their manufacturing, use and disposal poses a risk to the environment and

public health. The evaluation of the legislation showed that strengthening of existing

measures to reduce the impact of medicinal products' lifecycle on the environment and public

health is required. Measures under this Regulation complement the main environmental

legislation, in particular the Water Framework Directive (2000/60/EC14), the Environmental

Quality Standard Directive (2008/105/EC15) the Groundwater Directive (2006/118/EC16), the

Urban Wastewater Treatment Directive (91/271/EEC17), the Drinking Water Directive

(2020/218418) and the Industrial Emissions Directive (2010/75/EU19).

Directive 2000/60/EC of the European Parliament and of the Council of 23 October 2000 establishing
a framework for Community action in the field of water policy (OJ L 327, 22.12.2000, p. 1).

Directive 2008/105/EC of the European Parliament and of the Council of 16 December 2008 on
environmental quality standards in the field of water policy, amending and subsequently repealing
Council Directives 82/176/EEC, 83/513/EEC, 84/156/EEC, 84/491/EEC, 86/280/EEC and amending
Directive 2000/60/EC of the European Parliament and of the Council (OJ L 348, 24.12.2008, p. 84).

Directive 2006/118/EC of the European Parliament and of the Council of 12 December 2006 on the
protection of groundwater against pollution and deterioration (OJ L 372, 27.12.2006, p. 19).

Council Directive 91/271/EEC of 21 May 1991 concerning urban waste-water treatment (OJ L 135,
30.5.1991, p. 40).

Directive (EU) 2020/2184 of the European Parliament and of the Council of 16 December 2020 on the
quality of water intended for human consumption (recast) (OJ L 435, 23.12.2020, p. 1).

Directive 2010/75/EU of the European Parliament and of the Council of 24 November 2010 on
industrial emissions (integrated pollution prevention and control) (recast) (OJ L 334, 17.12.2010, p.
17).

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(70) Marketing authorisation applications for medicinal products in the Union should include an

Environmental Risk Assessment (ERA) and risk mitigation measures. If the applicant fails to

submit a complete or sufficiently substantiated environmental risk assessment or they do not

propose risk mitigation measures to sufficiently address the risks identified in the

environmental risk assessment, the marketing authorisation should be refused unless the

necessary information can be obtained through post-authorisation studies or

appropriate risk mitigating measures can be implemented as a condition to marketing

authorisation. The ERA should be updated when new data or knowledge about relevant risks

become available.

(71) Marketing authorisation applicants should take into account environmental risk assessment

procedures of other EU legal frameworks that may apply to chemicals dependent on their use.

Further to this Regulation, there are four main other frameworks: (i) Industrial chemicals

(REACH, (Regulation (EC) No 1907/2006); (ii) Biocides (Regulation (EC) No 528/2012);

(iii) Pesticides (Regulation (EC) No 1107/2009); and (iv) Veterinary medicines (Regulation

(EU) 2019/6)). As a part of the Green Deal, the Commission has proposed a ‘one-substance

one-assessment’ (OS-OA) approach for chemicals20, in order to increase the efficiency of the

registration system, reduce costs and unnecessary animal testing.

(72) The emissions and discharges of antimicrobials to the environment from manufacturing sites

may lead to antimicrobial resistance (“AMR”), which is a global concern regardless where the

emissions and discharges take place. Therefore, the ERA scope should be extended to cover

the risk of AMR selection during the entire life cycle of antimicrobials, including

manufacturing.

Communication from the Commission to the European Parliament, the European Council, the Council,
the European Economic and Social Committee and the Committee of the Regions, The European
Green Deal, Brussels (2019), COM(2019) 640 final.

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(73) The proposal also includes provisions for a risk-based approach regarding the ERA

obligations of marketing authorisation holders before October 2005 and the setting-up of an

ERA monograph system for active substances. This ERA monograph system should be

available to applicants for use when conducting an ERA for a new application.

(74) For medicinal products authorised prior to October 2005, without any ERA, specific

provisions should be introduced to set up a risk based prioritisation programme for the ERA

submission or update by the market authorisation holders. For generic, biosimilar, hybrid

and bio-hybrid medicinal products and fixed-dose combinations, for which the reference

medicinal product has been authorised before 30 October 2005, and which are included

in this programme, the ERA should be submitted after the outcome of the ERA of such

reference medicinal product is made publicly available by the Agency.

(75) Cyprus, Ireland, Malta and Northern Ireland hasve historically relied on the supply of

medicinal products from or through parts of the United Kingdom other than Northern Ireland.

Following the withdrawal of the United Kingdom of Great Britain and Northern Ireland from

the European Union and the European Atomic Energy Community, to prevent shortages of

medicinal products and ultimately to ensure a high level of public health protection, specific

provisions derogations to this Directive have been put in place need to be included for

medicinal products supplied to Cyprus, Ireland, Malta and Northern Ireland from or through

parts of the United Kingdom other than Northern Ireland. In order to ensure uniform

application of Union law in the Member States, the derogations applicable in Cyprus, Ireland

and Malta should be of a temporary nature only.

(76) To ensure that all children in the Union have access to the products specifically authorised for

paediatric use, when an agreed paediatric investigation plan has led to the authorisation of a

paediatric indication for a product already marketed for other therapeutic indications, the

marketing authorisation holder should be obliged to place the product in the same markets

within two years of the date of approval of the indication.

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(77) It is necessary in the interest of public health to ensure the continuing availability of safe and

effective medicinal products authorised for paediatric indications. Therefore, if a marketing

authorisation holder intends to withdraw such a medicinal product from the market then

arrangements should be in place so that the paediatric population can continue to have access

to the medicinal product in question. In order to help achieve this, the Agency should be

informed in good time of any such intention and should make that intention publicly

available.

(78) To avoid unnecessary administrative and financial burdens both for the marketing

authorisation holders and the competent authorities, certain streamlining measures should be

introduced, in line with the digital by default principle. Electronic application for marketing

authorisation and for variations to the terms of the marketing authorisation should be

introduced.

(79) As a general rule, risk management plans for generic and biosimilar medicinal products

should not be developed and submitted, considering that the reference medicinal product has

such a plan, except in specific cases, where a risk management plan should be provided.

Furthermore, as a general rule a marketing authorisation should be granted for an unlimited

period; exceptionally, one renewal may be decided only on justified grounds related to the

safety of the medicinal product. In addition the risk management plan for hybrid and bio-

hybrid medicinal products should be limited to the differences between this medicinal

product and the reference medicinal product, as indicated in the application for the

marketing authorisation, provided that no additional risk minimisation measures exist

for the reference medicinal product and provided that the marketing authorisation for

the reference medicinal product has not been withdrawn prior to the submission of the

application.

(80) In the event of a risk to public health, the marketing authorisation holder or the competent

authorities should be able to make urgent safety or efficacy restrictions on their own initiative.

In such case, when the referral procedure is launched, any duplication of assessment should

be avoided.

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(81) To address patients’ needs, an increasing number of innovative medicinal products derive

from or are combined with other products that may be manufactured or tested and regulated

under more than one Union legal framework. Similarly, the same sites are increasingly

overseen by the authorities established under different Union legal frameworks. To ensure

safe and efficient production and supervision of such products and to allow an appropriate

delivery to patients, it is important to ensure coherence. The coherence and sufficient

alignment can only be ensured through appropriate cooperation in the development of the

practices and principles applied under the different Union legal frameworks. An appropriate

cooperation should therefore be embedded within several provisions of this Directive, such as

those regarding classification advice, oversight, or the development of guidelines.

(82) For products that combine a medicinal product and a medical device, including in vitro

diagnostics medical device, the applicability of the two respective regulatory frameworks

should be specified and the appropriate interaction between the three two applicable

regulatory frameworks should be ensured. The same should apply to combinations of medical

products and products other than medical devices.

(83) To ensure that the competent authorities have all the information needed for their assessment

in the case of integral combinations of a medicinal product with a medical device, including

in vitro diagnostics medical device, or of combinations of a medicinal product with a

product other than a medical device, the marketing authorisation applicant shall submit data

establishing the safe and effective use of the integral combination of the medicinal product

with the medical device, including in vitro diagnostics medical device, or of the

combination of a medicinal product with the other product. The competent authority should

assess the benefit-risk balance of the integral combination taking into account the suitability

of the use of the medicinal product together with the medical device, in vitro diagnostics

medical device or the other product.

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(84) To ensure that the competent authorities have all the information needed for their assessment

of medicinal products in exclusive use with a medical device or in vitro diagnostics medical

device (that is to say medicinal products that are presented in a package with a medical device

or that are to be used with a medical device referenced in the summary of product

characteristics) the marketing authorisation applicant shall submit data establishing the safe

and effective use of the medicinal product taking into account its use with the medical device

or in vitro diagnostics medical device. The competent authority should assess the benefit-

risk balance of the medicinal product, also taking into account the use of the medicinal

product with the medical device.

(85) The Directive also clarifies that a medical device that is part of an integral combination has to

comply with the general safety and performance requirements set out in Annex I of

Regulation (EU) 2017/745 of the European Parliament and of the Council21. A medical device

in exclusive use with a medical device needs to meet all of the requirements of Regulation

(EU) 2017/745. A medicinal product in exclusive use with a medical device that is not

ancillary to that of the medical device shall comply with the requirements of this Directive

and of the [revised Regulation (EC) No 726/2004] taking into account its use with the medical

device, without prejudice to the specific requirements of the Regulation (EU) 2017/745 and

of the Regulation (EU) 2017/746 22, as applicable.

Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical
devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and

Regulation (EC) No

1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC (OJ L 117, 5.5.2017, p. 1).

Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in
vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision
2010/227/EU (OJ L 117, 5.5.2017, p. 176–332)

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(86) For all these products (integral combinations of a medicinal product and a medical device or

in vitro diagnostic medical device, medicinal products in exclusive use with medical devices

and combinations of a medicinal product with a product other than a medical device) the

competent authority should also be able to request the marketing authorisation applicant to

transmit any additional information needed and the marketing authorisation applicant should

be bound to submit any such information requested. For medicinal product in exclusive use

with a medical device that is not ancillary to that of the medical device, the marketing

authorisation applicant shall also, upon request from the competent authority, submit any

additional information related to the medical device taking into account its use with the

medicinal product and that is relevant for the post-authorisation monitoring of the medicinal

product, without prejudice to the specific requirements of the [revised Regulation (EC) No

726/2004].

(87) For integral combination of a medicinal product with a medical device and for combinations

of a medicinal product with a product other than a medical device, the marketing authorisation

holder should also bear the overall responsibility for the whole product in terms of

compliance of the medicinal product with the requirements of this Directive and the [revised

Regulation(EC) No 726/2004] and should ensure coordination of the information flow

between the sectors throughout the assessment procedure and the lifecycle of the medicinal

product.

(88) In order to ensure the quality, safety and efficacy of medicinal product at all stages of

manufacturing and distribution the marketing authorisation holder shall be responsible, when

necessary to trace back an active substance, excipient or any other substance that used in the

manufacturing of medicinal product and intended to be part of the medicinal product or

expected to be present in the medicinal product, for example impurities, degradation products

or contaminants.

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(89) In the interests of public health marketing authorisation holders should be able to ensure the

traceability of any substance that is used, intended or expected to be present in a medicinal

product at all stages of manufacturing and distribution, and identify any natural or legal

person from whom they have been supplied these substances. Therefore, procedures and

systems should be placed to provide that information in case it should be necessary with the

view of quality, safety or efficacy of medicinal products.

(90) It is recognised that the development of pharmaceuticals is an area where neither science, nor

technology stand still. The last decades have seen new categories of medicinal products

emerging from biological medicinal products to biosimilars or advanced therapy medicinal

products or in the future phages therapies. Those categories of products may in some

instances require adapted rules to fully take account of their specific characteristics. For that

reason a forward looking legal framework should include provisions to enable such adapted

frameworks subject to strict criteria and under a Commission empowerment guided by the

scientific input of the European Medicines Agency.

(91) The adaptations may entail adapted, enhanced, waived or deferred requirements compared to

standard medicinal products. They could in particular include changes to the dossier

requirements for such medicinal products, the way their quality, safety and efficacy is

demonstrated by applicants or tailored manufacturing controls and good manufacturing

practices requirements, as well as additional control methods prior and during their

administration and use. The adaptions should however not go beyond what is necessary for

the attainment of the objective of adaptation to the specific characteristics.

(92) In order to increase the preparedness and responsiveness against health threats, in particular

the emergence of antimicrobial resistance, adapted frameworks may be relevant to facilitate

the rapid change of antimicrobials composition to maintain their efficacy. The use of

established platforms would allow efficient and timely adaptation of those medicinal products

to the clinical context.

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(93) To optimise the use of resources for both applicants for marketing authorisation and

competent authorities and avoid duplication of assessment of chemical active substances of

medicinal products, marketing authorisation applicants should be able to rely on an active

substance master file certificate or a certificate of suitability to the monograph of the

European Pharmacopeia, instead of submitting the relevant data as required in accordance

with Annex II. An active substance master file certificate may be granted by the Agency when

the relevant data on the active substance concerned is not already covered by a monograph of

the European Pharmacopeia or by another active substance master file certificate. Where a

certificate of suitability to the monographs of the European Pharmacopoeia or an active

substance master file certificate is used as part of the marketing authorisation

application, there may be a need to provide additional quality data that are not covered

by those processes, as part of the marketing authorisation dossier to demonstrate the

suitability of the active substance in the context of its intended use in the medicinal

product. The Commission should be empowered to establish the procedure for the single

assessment of an active substance master file. To further optimise the use of resources, the

Commission should be empowered to allow use a certification scheme also for additional

quality master files i.e. for active substances other than chemical active substances, or for

other substances present or used in the manufacture of a medicinal product, required in

accordance with Annex II, e.g. in case of novel excipients, adjuvants, radiopharmaceutical

precursors and active substance intermediates, when the intermediate is a chemical active

substance by itself or used in conjugation with a biological substance.

(94) For reasons of public health and legal consistency, and with a view to reducing the

administrative burden and strengthening predictability for economic operators, variations to

all types of marketing authorisations should be subject to harmonised rules.

(95) The terms of a marketing authorisation for a medicinal product may be varied, after it has

been granted. While the core elements of a variation are laid down in this Directive, the

Commission should be empowered to complement these elements by laying down further

necessary elements, to adapt the system to scientific and technological progress, including

digitalisation, and to ensure that unnecessary administrative burden is avoided for both the

marketing authorisation holders and competent authorities.

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(96) Scientific and technological progresses in data analytics and data infrastructure provide

valuable support to the development, authorisation and supervision of medicinal products.

The digital transformation has affected regulatory decision-making, making it more data-

driven and multiplying the possibilities for regulatory authorities to access evidence, across

the lifecycle of a medicinal product. This Directive recognises the competent authorities of

the Member States’ capacity to access and analyse data submitted independently from the

marketing authorisation applicant or marketing authorisation holder. On this basis, competent

authorities of the Member States should take initiative to update the summary of product

characteristics in case new efficacy or safety data impacts the benefit-risk balance of a

medicinal product.

(97) Access to individual patient data from clinical studies in structured format allowing for

statistical analyses can is valuable to assist regulators in understanding the submitted

evidence and to inform regulatory decision-making on the benefit-risk balance of a medicinal

product. The introduction of such possibility in the legislation is important to further enable

data-driven benefit-risk assessments at all stages of the lifecycle of a medicinal product. This

Directive therefore empowers competent authorities of Member States to request, as

necessary, such data as part of the assessment of initial and post-marketing authorisation

applications..

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Due to the sensitive nature of health data, the competent authorities should safeguard its

processing operations and ensure that they respect the data protection principles of lawfulness,

fairness and transparency, purpose limitation, data minimisation, accuracy, storage limitation,

integrity and confidentiality. Where the processing of personal data is necessary for the

purposes of this Directive, such processing should be done in accordance with Union law on

the protection of personal data. Any processing of personal data under this Directive should

take place in accordance with Regulation (EU) 2016/67923 and Regulation (EU) 2018/172524

of the European Parliament and of the Council.

(98) Pharmacovigilance rules are necessary for the protection of public health in order to prevent,

detect and assess adverse reactions to medicinal products placed on the Union market, as the

full safety profile of medicinal products can only be known after they have been placed on the

market.

(99) In order to ensure the continued safety of medicinal products in use, it is necessary to ensure

that pharmacovigilance systems in the Union are continually adapted to take account of

scientific and technical progress.

(100) It is necessary to take account of changes arising as a result of international harmonisation of

definitions, terminology and technological developments in the field of pharmacovigilance.

(101) The increasing use of electronic networks for communication of information on adverse

reactions to medicinal products marketed in the Union is intended to allow competent

authorities to share the information at the same time.

Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the
protection of natural persons with regard to the processing of personal data and on the free movement
of such data, and repealing Directive 95/46/EC (General Data Protection Regulation) (OJ L 119,
4.5.2016, p. 1).

Regulation (EU) 2018/1725 of the European Parliament and of the Council of 23 October 2018 on the
protection of natural persons with regard to the processing of personal data by the Union institutions,
bodies, offices and agencies and on the free movement of such data, and repealing Regulation (EC) No
45/2001 and Decision No 1247/2002/EC (OJ L 295, 21.11.2018, p. 39).

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(102) It is the interest of the Union to ensure that the pharmacovigilance systems for centrally

authorised medicinal products and those authorised by other procedures are consistent.

(103) Marketing authorisation holders should be proactively responsible for on-going

pharmacovigilance of the medicinal products they place on the market.

(104) The use of colours in human and veterinary medicinal products is currently regulated by

Directive 2009/35/EC of the European Parliament and of the Council25, and restricted to those

authorised in accordance with Regulation (EC) No 1333/2008 of the European Parliament and

of the Council on food additives26, for which specifications are laid down in Commission

Regulation (EU) No 231/201227. Uses of excipients other than colours in medicinal products

are subject to the Union rules on medicinal products and are evaluated as part of the overall

benefit risk profile of a medicinal product.

(105) Experience has shown the need to maintain to a certain extent the principle of the use in

medicinal products of those colours authorised as food additives. However, it is also

appropriate to foresee a specific assessment for the use of the colour in medicines when a

food additive is removed from Union list of food additives. Therefore, in this specific case,

EMA should carry out its own assessment for the use of the colour in medicines, taking into

account the EFSA opinion and its underlying scientific evidence, as well as any additional

scientific evidence and giving particular consideration to the use in medicines. EMA should

also be responsible for following any scientific evidence for the colours retained for specific

medicine use only. Directive 2009/35/EC should therefore be repealed.

Directive 2009/35/EC of the European Parliament and of the Council of 23 April 2009 on the
colouring matters which may be added to medicinal products (OJ L 109, 30.4.2009, p. 10).

Regulation (EC) No 1333/2008 of the European Parliament and of the Council of 16 December 2008
on food additives (OJ L 354, 31.12.2008, p. 16).

Commission Regulation (EU) No 231/2012 of 9 March 2012 laying down specifications for food
additives listed in Annexes II and III to Regulation (EC) No 1333/2008 of the European Parliament
and of the Council (OJ L 83, 22.3.2012, p. 1).

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(106) With regard to the supervision and inspections, manufacturing and import of starting materials

or intermediate and also of functional excipient shall be under surveillance due to their

ancillary action to the active substance and to their possible impact to the quality, safety and

efficacy to the medicinal products.

(107) The main purpose of any regulation on the manufacture and distribution of medicinal products

should be to safeguard public health.

(108) It should be ensured that, in the Member States, the supervision and control of the

manufacture and the distribution of medicinal products is carried out by official

representatives of the competent authority who fulfils minimum conditions of qualification.

(109) There may be cases where manufacturing or testing steps of medicinal products need to take

place in sites close to patients considering properties of the medicinal product, for example

advanced therapy medicinal products with short shelf-life, where deemed appropriate for a

medicinal product by the national authority competent or the Agency for authorising of

the placing on the market of such medicine during the authorisation procedure. In such

cases, these manufacturing or testing steps may need to be decentralised to multiple sites to

reach patients across the Union. When the manufacturing or testing steps are decentralised,

they should be carried out under the responsibility of the qualified person of an authorised

central site. The decentralised sites should not require a separate manufacturing authorisation

from the one granted to the relevant central site but should be registered by the competent

authority of the Member State in which the decentralised site is established and supervised

by this authority. In the case of medicinal products containing, consisting or derived from

autologous SoHO, the decentralised sites have to be registered as a SoHO entity as defined in

and pursuant to [SoHO Regulation] for the activities of donor review and eligibility

assessment, donor testing and collection, where applicable or just for collection in the case of

products manufactured for autologous use.

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(110) The quality of medicinal products manufactured or available in the Union should be

guaranteed by requiring that the active substances used in their composition comply with the

principles of good manufacturing practice in relation to those medicinal products. It has

proved necessary to reinforce the Union provisions on inspections and to compile a Union

database of the results of those inspections.

(111) Verification of compliance with the legal requirements of manufacturing, distribution and use

of medicinal products by relevant entities through a system of supervision, is of fundamental

importance to ensure that the objectives of this Directive are effectively achieved. Therefore,

the competent authorities of the Member States should have the power to perform on site or

remote inspections, as part of the system of supervision at all stages of manufacturing,

distribution and use of medicinal products or active substances and rely on the outcome of

inspections conducted by trusted third countries competent authorities. To preserve the

effectiveness of the inspections, the competent authorities should have the possibility to

perform joint inspections and also, where necessary, unannounced inspections.

(112) The frequency of controls should be established by the competent authorities having regard to

the risk and to the level of compliance expected in different situations. That approach should

allow those competent authorities to allocate resources where the risk is the highest. In some

cases, the system of supervision should be applied irrespective of the level of risk or

suspected non-compliance, for example prior to granting manufacturing authorisations.

(113) Within the procedure for "Certification of Suitability to the monographs of the European

Pharmacopoeia" the European Directorate for the Quality of Medicines and Healthcare

verifies by means of inspections whether the data submitted by the applicant established by

the Council of Europe confirms the suitability of monographs to control the chemical purity,

microbiological quality and TSE risk (if relevant). It also verifies whether the manufacturing

complies with good manufacturing practice for active substances. Depending of the outcome

of the inspection, a certificate of compliance or non-compliance of good manufacturing

practice, is issued by the European Directorate for the Quality of Medicines and Healthcare or

by the Member State participating in the inspection.

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(114) Each undertaking that manufactures or imports medicinal products should set up a mechanism

to ensure that all information supplied about a medicinal product conforms to the approved

conditions of use.

(115) The conditions governing the supply of medicinal products to the public should be

harmonised.

(116) In this connection persons moving around within the Union have the right to carry a

reasonable quantity of medicinal products lawfully obtained for their personal use. It should

also be possible for a person established in one Member State to receive from another

Member State a reasonable quantity of medicinal products intended for their personal use.

(117) By virtue of [revised Regulation (EC) No 726/2004], certain medicinal products are the

subject of a Union marketing authorisation. In this context, the prescription status of

medicinal products covered by a Union marketing authorisation needs to be established. It is

therefore important to set the criteria on the basis of which Union decisions will be taken.

(118) It is therefore appropriate to harmonise the basic principles applicable to the prescription

status of medicinal products in the Union or in the Member State concerned, while taking as a

starting point the principles already established on this subject by the Council of Europe as

well as the work of harmonisation completed within the framework of the United Nations,

concerning psychotropic or narcotic substances - the United Nations Single Convention of

1961 on narcotic drugs and Convention on Psychotropic Substances of 1971.

(119) Many operations involving the wholesale distribution of medicinal products may cover

several Member States simultaneously.

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(120) It is necessary to exercise control over the entire chain of distribution of medicinal products,

from their manufacture or import into the Union through to supply to the public, so as to

guarantee that such products are stored, transported and handled in suitable conditions. The

requirements that should be adopted for this purpose will considerably facilitate the

withdrawal of defective products from the market and allow more effective efforts against

counterfeit products.

(121) Any person involved in the wholesale distribution of medicinal products should be in

possession of a special authorisation. Pharmacists and persons authorised to supply medicinal

products to the public, and who confine themselves to this activity, should be exempt from

obtaining this authorisation. It is however necessary, in order to control the complete chain of

distribution of medicinal products, that pharmacists and persons authorised to supply

medicinal products to the public keep records showing transactions in products received.

(122) Marketing authorisation is to be subject to certain essential conditions and it is the

responsibility of the Member State concerned to ensure that such conditions are met; whereas

each Member State is to recognize authorisations granted by other Member States.

(123) Certain Member States impose on wholesalers who supply medicinal products to pharmacists

and on persons authorised to supply medicinal products to the public certain public service

obligations. Those Member States should be able to continue to impose those obligations on

wholesalers established within their territory. They should also be able to impose them on

wholesalers in other Member States on condition that they do not impose any obligation more

stringent than those that they impose on their own wholesalers and provided that such

obligations may be regarded as warranted on grounds of public health protection and are

proportionate in relation to the objective of such protection.

(124) Rules should be laid down as to how the labelling and package leaflets are to be presented.

(125) The provisions governing the information supplied to users should provide a high degree of

consumer protection, in order that medicinal products may be used correctly on the basis of

full and comprehensible information.

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(126) The marketing of medicinal products whose labelling and package leaflets comply with this

Directive should not be prohibited or impeded on grounds connected with the labelling or

package leaflet.

(127) The use of electronic and technological possibilities other than paper package leaflets can

facilitate access to medicinal products, medicinal products distribution and should always

guarantee equal or better quality of information to all patients compared to the paper form of

product information.

(128) Member States have varying levels of digital literacy and internet access. In addition, patient

and healthcare professional needs may differ. It is therefore necessary that Member States

have a discretion to maintain the paper package leaflet in parallel toon the adoption of

measures enabling the electronic provision of product information. It is necessary to while

ensureing that no patient is left behind, taking into account the needs of different age

categories and the different levels of digital literacy in the population, and making sure that

product information is easily accessible to all patients. Member States should when

appropriate, progressively consider allowing the possibility for providing product

information only in electronic version product information, while ensuring full compliance

with the rules on protection of personal data, and adhere to harmonised standards developed at

EU level with regard to all or specific categories of medicinal products.

(129) Where Member States decide that the package leaflet should be made available in principle

only electronically, they should also ensure that a paper version of the package leaflet is to be

made available on demand and without additonal cost to patients. They should also ensure

that the information in digital format is easily accessible to all patients, for instance by

including in the outer packaging of the product a digitally readable barcode, which would

direct the patient to the electronic version of the package leaflet.

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(130) The use of multi-language, or multi-country packages can be a tool for access to medicinal

products, in particular for small markets and in public health emergencies. Where multi-

language, or multi-country packages are used, Member States may also allow the use on the

labelling and package leaflet of an official language of the Union that is commonly

understood in the Member States where the multi-language, or multi-country package is

marketed.

(131) To ensure a high level of transparency of public support to the research and development of

medicinal products, the reporting of public contribution for the development of a particular

medicinal product should be a requirement for all medicines. Given however the practical

difficulty to identify how indirect public funding instruments, such as tax advantages, have

supported a particular product, the reporting obligation should only concern the direct public

financial support, such as direct grants or contracts. Therefore, the provisions of this Directive

ensure, without prejudice to the rules on the protection of confidential and personal data,

transparency regarding any direct financial support received from any public authority or

public body to carry out any activities for the research and development of medicinal

products.

(132) To ensure the accuracy of the information made publicly available by the marketing

authorisation holder, the declared information has to be subject to audit by an independent

auditor.

(133) In order to ensure a harmonised and consistent reporting of public contribution for the

development of a particular medicinal products, the Commission should be able to adopt

implementing acts to clarify the principles and format that the marketing authorisation holder

should adhere to when reporting this information.

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(134) This Directive is without prejudice to the application of measures adopted pursuant to

Directive 2006/114/EC of the European Parliament and of the Council28 or pursuant to

Directive 2005/29/EC of the European Parliament and of the Council29. Therefore the

provisions regarding the advertising of medicinal products of this Directive should therefore

be considered, where relevant, as a lex specialis with respect to Directive 2005/29/EC.

(135) Advertising, even of medicinal products not subject to a prescription, could affect public

health and distort competition. Therefore, advertising of medicinal products should meet

certain criteria. Persons qualified to prescribe, administer or supply medicinal products can

properly evaluate the information available in advertising because of their knowledge,

training and experience. The advertising of medicinal products to persons who cannot

properly assess the risk associated with their use may lead to medicinal product misuse or

overconsumption which is liable to harm public health.

Therefore advertisement to the general public of medicinal products that are available only on

medical prescription should be prohibited. Furthermore, distribution of samples free of charge

to the general public for promotional ends is to be prohibited, also teleshopping for medicinal

products shall be prohibited pursuant to Directive 2010/13/EU of the European Parliament

and of the Council30. It should be possible within certain restrictive conditions to provide

samples of medicinal products free of charge to persons qualified to prescribe or supply them

so that they can familiarise themselves with new products and acquire experience in dealing

with them.

Directive 2006/114/EC of the European Parliament and of the Council of 12 December 2006
concerning misleading and comparative advertising (OJ L 376, 27.12.2006, p. 21).

Directive 2005/29/EC of the European Parliament and of the Council of 11 May 2005 concerning
unfair business-to-consumer commercial practices in the internal market and amending Council
Directive 84/450/EEC, Directives 97/7/EC, 98/27/EC and 2002/65/EC of the European Parliament and
of the Council and Regulation (EC) No 2006/2004 of the European Parliament and of the Council
(‘Unfair Commercial Practices Directive’) (OJ L 149, 11.6.2005, p. 22).

Directive 2010/13/EU of the European Parliament and of the Council of 10 March 2010 on the
coordination of certain provisions laid down by law, regulation or administrative action in Member
States concerning the provision of audiovisual media services (Audiovisual Media Services Directive)
(OJ L 095 15.4.2010, p. 1).

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(136)

Advertising of medicinal products should aim at disseminating objective and unbiased

information about the medicinal product. For that purpose, it is expressly forbidden highlight

negatively another medicinal product or to suggest that advertised medicinal product might be

safer or more effective than another medicinal product. Comparison of medicinal products

should only be allowed if such information is listed in the summariesy of product

characteristics of the concerned medicinal products being advertised. This prohibition covers

any medicinal product, also biosimilars, and therefore it would be misleading to refer in the

advertising, that a biosimilar medicinal product would not be interchangeable with the

original biological medicinal product or another biosimilar from the same original biological

medicinal product. Additional strict rules about negative and comparative advertising of

competitor medicinal products will prohibit claims that can mislead persons qualified to

prescribe, administer or supply them.

(137) The dissemination of information which encourages the purchase of medicinal products

should be considered within the concept of advertising of medicinal products, even where that

information does not refer to a specific medicinal product, but to unspecified medicinal

products.

(138) Advertising of medicinal products should be subject to strict conditions and effective,

adequate monitoring. Reference in this regard should be made to the monitoring mechanisms

set up by Directive 2006/114/EC.

(139) Medical sales representatives have an important role in the promotion of medicinal products.

Therefore, certain obligations should be imposed upon them, in particular the obligation to

supply the person visited with a summary of product characteristics.

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(140) Innovative, ‘combination medicinal products’ and other developed medicinal products are

complex in regards to their composition and administration. Therefore, in addition to persons

qualified to prescribe medicinal products, also persons qualified to administer medicinal

products need to be familiar with all characteristics of those medicinal products, especially

with safe administration and use, including the comprehensive instructions to the patients. For

that purpose information about medicinal products subject to medical prescription is also

clearly allowed to persons qualified to administer them.

(141) Persons qualified to prescribe, administer or supply medicinal products should have access to

a neutral, objective source of information about products available on the market. Whereas it

is nevertheless for the Member States to take all measures necessary to this end, in the light of

their own particular situation.

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(141a) In order to avoid waste, reduce the burden on the environment, mitigate shortages and

realise cost savings, it is feasible to allow redispensing of medicinal products, under

strict conditions. Through the practice of redispensing, a pharmacy can take back and

redispense a medicinal product that has already been supplied to a patient. Member

States should ensure that the redispensing can only be done by the same pharmacy that

initially supplied the product. This creates a closed loop and the medicinal products will

not re-enter the European Medicines Verification System (EMVS). Pharmacy can only

redispense medicinal products to a named patient on the basis of informed consent. The

returned products can be redispensed only after the pharmacy has verified that the

medicinal product concerned is not a falsified medicinal product, that the expiration

date has not been exceeded and the package has been stored under the right conditions.

To check these parameters, instruments such as a temper proof bag and temperature

logger can be used.The pharmacy must record the medicinal product and the recipient

for the purpose of inspections. Redispensing might not be feasible for all medicinal

products. Member States should be able to identify and list in national legislation which

categories specific of products are allowed to be redispensed in that Member State, such

as oral oncological medicinal products, which could provide for a pilot category since

such products do not have strict storage requirements. Member States should lay down

rules rules on liability for potential damages resulting from the use of the medicinal

products that have been redispensed when such damages are a consequence of failure to

ensure appropriate storage and transport conditions between the initially dispensing

and returning to the pharmacy, or a failure to ensure that the product re-dispensed has

not been falsified. The provision in this Directive does not affect the possibility for

Member States to set additional restrictive conditions under which medicinal products

may be redispensed. Member States should ensure that the collection, re-dispensing will

not be used for obtaining economic gains and preventing penetration of the re-dispensed

medicines to the supply chain.

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(142) In order to ensure that information on the use of the medicinal products in children are

appropriately taken into account at the moment of marketing authorisation, it is therefore

necessary to introduce a requirement for new medicinal products or when developing

paediatric indications of already authorised products covered by a patent or a supplementary

protection certificate, to present either the results of studies in the paediatric population in

accordance with an agreed paediatric investigation plan or proof of having obtained a waiver

or deferral, at the time of filing a marketing authorisation application or an application for a

new therapeutic indication, new pharmaceutical form or new route of administration. In order

to ensure that the data supporting the marketing authorisation concerning the use of a product

in children are adequate, the competent authorities responsible for the authorisation of a

medicinal product should check compliance with the agreed paediatric investigation plan and

any waivers and deferrals at the validation step for marketing authorisation applications.

(143) To provide healthcare professionals and patients with information on the safe and effective

use of medicinal products in the paediatric population, the results of the studies conducted in

accordance with a paediatric investigation plan, independently from the fact that they support

or not the use of the medicinal product in children, appropriate information should be

included in the summary of product characteristics and, if appropriate, in the package leaflet.

Information on waivers should also be included in product information. When all the

measures in the paediatric investigation plan have been complied with, that fact should be

recorded in the marketing authorisation, and that should then be the basis upon which

companies can obtain rewards.

(144) Relevant data and information collected through clinical studies conducted before the

introduction in the Union of a paediatric medicines Regulation and received by the competent

authorities should be assessed without undue delay and taken into consideration for eventual

variation of existing marketing authorisations.

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(145) In order to ensure uniform conditions for the implementation of this Regulation,

implementing powers should be conferred on the Commission. Those powers should be

exercised in accordance with Regulation (EU) No 182/2011 of the European Parliament and

of the Council31.

(146) Due to the need to reduce overall approval times for medicinal products, the time between the

opinion of the Committee for Medicinal Products for Human Use (CHMP) and the final

decision on any Commission Decision concerning national marketing authoristions, in

particular for referrals, should be reduced to, in principle, 46 days.

(147) On the basis of the opinion of the Agency, the Commission should adopt a decision on the

referral by means of implementing acts. In justified cases, the Commission may return the

opinion for further examination or deviate in its decision from the opinion of the Agency.

Taking into account the need to make medicinal products swiftly available to patients, it

should be acknowledged that the chairperson of the Standing Committee for Medicines for

Human Use will use the available mechanisms under Regulation 182/2011 and notably the

possibility to obtain the committees opinion in written procedure and within expeditious

deadlines which, in principle, will not exceed 105 calendar days.

(148) The Commission should be empowered to adopt any necessary changes to Annex II in order

to take into account scientific and technical progress.

Regulation (EU) No 182/2011 of the European Parliament and of the Council of 16 February 2011
laying down the rules and general principles concerning mechanisms for control by Member States of
the Commission’s exercise of implementing powers (OJ L 55, 28.2.2011, p. 13).

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(149) In order to supplement or amend certain non-essential elements of this Directive, the power to

adopt acts in accordance with Article 290 TFEU should be delegated to the Commission in

respect of specifying the procedure for examination of application of active substance master

file certificate, the publication of such certificates, the procedure for changes to the active

substance master file and its certificate, access to the active substance master file and its

assessment report; specifying additional quality master files to provide information on a

constituent of a medicinal product, the procedure for examination of application of a quality

master file certificate, the publication of such certificates, the procedure for changes to the

quality master file and its certificate, and access to the quality master file and its assessment

report; determining the situations in which post-authorisation efficacy studies may be

required; specifying the categories of medicinal products to which a marketing authorisation

subject to specific obligations could be granted and specifying the procedures and

requirements for granting such a marketing authorisation and for its renewal; specifying

exemptions to variation and the categories in which variations should be classified and

establishing procedures for the examination of applications for variations to the terms of

marketing authorisations as well as specifying conditions and procedures for cooperation with

third countries and international organisations for examination of applications for such

variations. It is of particular importance that the Commission carry out appropriate

consultations during its preparatory work, including at expert level, and that those

consultations be conducted in accordance with the principles laid down in the

Interinstitutional Agreement of 13 April 2016 on Better Law-Making32. In particular, to

ensure equal participation in the preparation of delegated acts, the European Parliament and

the Council receive all documents at the same time as Member States’ experts, and their

experts systematically have access to meetings of Commission expert groups dealing with the

preparation of delegated acts.

OJ L 123, 12.5.2016, p. 1.

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(150) This Directive seeks to enable the right access to preventive healthcare and to benefit from

medical treatment under the conditions established by national laws and practices and to

ensure a high level of human health protection in the definition and implementation of all the

Union’s policies and activities as laid down in Article 35 of the Charter of Fundamental

Rights of the European Union.

(151) Since the objectives of this Directive, namely to establish rules on medicinal products

ensuring the protection of public health and the environment as well as the functioning of the

internal market, cannot be sufficiently achieved by the Member States as national rules would

lead to disharmonisation, unequal patient access to medicinal products and barriers to the

internal market, but can rather, by reason of its effects, be better achieved at Union level, the

Union may adopt measures, in accordance with the principle of subsidiarity as set out in

Article 5 of the Treaty on European Union. In accordance with the principle of

proportionality, as set out in that Article, this Directive does not go beyond what is necessary

in order to achieve those objectives.

(152) In accordance with the Joint Political Declaration of 28 September 2011 of Member States

and the Commission on explanatory documents33, Member States have undertaken to

accompany, in justified cases, the notification of their transposition measures with one or

more documents explaining the relationship between the components of a directive and the

corresponding parts of national transposition instruments. With regard to this Directive, the

legislator considers the transmission of such documents to be justified.

HAVE ADOPTED THIS DIRECTIVE:

OJ C 369, 17.12.2011, p. 14.

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Chapter I:

Subject matter, scope and definitions

Article 1

Subject matter and scope

This Directive lays down rules for the placing on the market, manufacturing, import, export,

supply, distribution, pharmacovigilance, advertising, supervision, control and use of

medicinal products for human use.

This Directive shall apply to medicinal products for human use intended to be placed on the

market.

In addition to the products referred to in paragraph 2, Chapter XI shall also apply to starting

materials, active substances, excipients and intermediate products.

In cases where, taking into account all its characteristics, a product falls within the definition

of a ‘medicinal product’ and within the definition of a product covered by other Union law

and there is a conflict between this Directive and other Union law, the provisions of this

Directive shall prevail.

The Directive shall not apply to:

(a) medicinal products prepared in a pharmacy in accordance with a medical prescription

or, regarding medicinal products that are available without medical prescription,

with an instruction of a doctor or another healthcare professional where provided

for in national law for an individual patient (‘magistral formula’);

(b) medicinal products prepared in a pharmacy in accordance with a pharmacopoeia and

intended to be supplied directly to the patients served by the pharmacy in question

(‘officinal formula’):;

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The exceptions under points (a) and (b) shall not apply for medicinal products

listed in points 1 and 2 of Annex I of the [revised Regulation (EU) 726/2004].

Member States may allow the supply of officinal formula by the pharmacy to a

hospital it serves, subject to the approval of the competent authority concerned.

(EU) No 536/2014

(d) substances of human origin, unless they fall within the definition of an advanced

therapy medicinal product or a SoHO-derived medicinal product other than

ATMPs.

Medicinal products referred to in paragraph 5, point (a), may be prepared in duly justified

cases in advance by a pharmacy serving a hospital, on the basis of the estimated medical

prescriptions or instruction as appropriate within that hospital for the following period of

up to seven days four weeks, taking into account the properties of the medicinal product.

Member States shall take the necessary measures to develop the production and use of

medicinal products derived from substances of human origin coming from voluntary unpaid

donations.

Without affecting the rules set out in Regulation (EU) 2024/1938, including as regards

the principle of voluntary and unpaid donations, Tthis Directive and all Regulations

referred to therein shall be without prejudice to the application of national legislation

prohibiting or restricting the use of any specific type of substance of human origin or animal

cells, or the sale, supply or use of medicinal products containing, consisting of or derived

from these animal cells or substances of human origin, on grounds not dealt with in the

aforementioned Union law. The Member States shall communicate the national legislation

concerned to the Commission.

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The provisions of this Directive shall not affect the powers of the Member States' authorities

either as regards the setting of prices for medicinal products or their inclusion in the scope of

national health insurance schemes, on the basis of health, economic and social conditions.

10. This Directive shall not affect the application of national legislation prohibiting or restricting

the following:

(a) the sale, supply or use of medicinal products as contraceptives or abortifacients;

(b) the use of any specific type of substance of human origin or animal cells, on grounds

not dealt with in the aforementioned Union law;

these animal cells or substances of human origin, on grounds not dealt with in Union

law.

The Member States shall communicate the national legislation concerned to the

Commission.

Article 2

Advanced therapy medicinal products prepared under hospital exemption

By way of derogation from Article 1(1), only this Article shall apply to advanced therapy

medicinal products prepared within the Member State on a non-routine basis in accordance

with the requirements set in paragraph 3 and used within the same Member State in a hospital

under the exclusive professional responsibility of a medical practitioner, in order to comply

with an individual medical prescription for a custom-made product for an individual patient

(‘advanced therapy medicinal products prepared under hospital exemption’).

The manufacturing and use of an advanced therapy medicinal product prepared under

hospital exemption shall require an approval by the competent authority of the Member State

(‘hospital exemption approval’). Member States shall notify any such approval, as well as

subsequent changes, to the Agency.

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The application for a hospital exemption approval shall be submitted to the competent

authority of the Member State where the hospital is located.

Member States shall ensure that advanced therapy medicinal products prepared under hospital

exemption comply with the requirements equivalent to the good manufacturing practices and

traceability for advanced therapy medicinal products referred to in Articles 5 and 15 of

Regulation (EC) No 1394/2007 34 respectively, and with pharmacovigilance requirements

equivalent to those provided for at Union level pursuant to [revised Regulation (EC) No

726/2004].

Member States shall ensure that data on the use, such as the number of patients and

product administrations, safety and the efficacy of advanced therapy medicinal products

prepared under hospital exemption is collected and reported in an aggregated manner by the

hospital exemption approval holder to the competent authority of the Member State at least

annually. The competent authority of the Member State shall review such data and shall verify

the compliance of advanced therapy medicinal products prepared under hospital exemption

with the requirements referred to in paragraph 3.

If a hospital exemption approval is revoked due to safety or efficacy concerns the competent

authority of the Member States that approved the hospital exemption shall inform the Agency.

The Agency shall inform and the competent authorities of the other Member States.

Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007
on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No
726/2004 (OJ L 324, 10.12.2007, p. 1).

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The competent authority of the Member State shall transmit the available data related to the

use, including the name of the active substance and categories of the advance therapy

medicinal product according Articles 2 of Regulation (EC) No 1394/20071, the indication

and the route of administration, the location of the use, as well as, safety and efficacy of

an advanced therapy medicinal product prepared under the hospital exemption approval to the

Agency annually. The Agency shall, in collaboration with the competent authorities of

Member States and the Commission, set up and maintain a repository of that data, including

the mechanism for electronic submission.

The Commission shall adopt implementing acts to specify the following:

(a) details of the application for the approval of hospital exemption referred to in paragraph

12, second subparagraph, including the evidence on quality, safety and efficacy of the

advance therapy medicinal products prepared under hospital exemption for the approval

and the subsequent changes;

(b) the content and format for collection and reporting of data referred to in paragraph 4

together with a description of such data;

holders within the same Member State or different Member States;

(d) the modalities for preparation and use of advanced therapy medicinal products under

hospital exemption on a non-routine basis.

Those implementing acts shall be adopted in accordance with the examination procedure

referred to in Article 214(2).

The Agency shall provide to the Commission a report on the experience acquired with the

hospital exemption approvals on the basis of contributions from Member States and the data

referred to in paragraph 4. The first report shall be provided three years after [OP please insert

the date =18 36 months after the date of entering into force of this Directive] and then every

five years thereafter.

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Article 3

Exceptions under certain circumstances

A Member State may, in order to fulfil special needs, exclude from the scope of this

Directive: medicinal products supplied in response to a bona fide unsolicited order or

anticipated bonafide unsolicited order, prepared formulated or used in accordance with

the specifications of an authorised healthcare professional and for use by to fullfil the needs

of an individual patients under their direct personal responsibility.

However, in such cases Member States shall encourage healthcare professionals and patients

to report data on the safety of the use of such products to the competent authority of the

Member State in accordance with Article 97.

For allergen medicinal products supplied in accordance with this paragraph, the competent

authorities of the Member State may request the submission of relevant information in

accordance with Annex II.

1a. In justified cases a Member State may temporarily exclude from the scope of this

Directive medicinal products prepared to mitigate or resolve a shortage in that Member

State, or to address the specific needs of the patients in that Member State in a situation

where a marketing authorisation holder has withdrawn the marketing authorisation of a

medicinal product for reasons unrelated to quality, safety or efficacy or to address a

situation, where there is an authorised medicinal product with a marketing

authorisation which does not cover the specific strength, pharmaceutical form or

formulation needed to address the specific needs of patients in that Member State.

The exceptions referred to in this paragraph shall apply only when no suitable

alternative medicinal product is authorised and available within that Member State or

can be supplied in accordance with paragraph 1 to meet the specific needs of the

patients, and in the case of shortage, when the shortage in the relevant Member State

cannot be resolved at that time through Union coordinated actions.

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For medicinal products prepared in accordance with this paragraph Member States

shall ensure that:

(a) the preparation of the medicinal product is approved by the national competent

authority on the basis of an assessment of the case and on public health grounds;

(b) in the case of a shortage, the approval under point (a) is revoked when the

shortage is resolved or the medicinal product can be supplied in accordance with

paragraph 1;

(c) in the cases other then shortages the approval is assessed at appropriate intervals

for the necessity of the exemption;

(d) appropriate oversight by the national competent authority is in place and in

particular any issues with regards to quality and safety are monitored and

evaluated;

(e) the facility preparing the medicinal product complies with the requirements of the

Good Manufacturing Practices referred to in Article 160;

(f)

the quality, safety and efficacy and the positive benefit-risk balance of the

medicinal product is confirmed by the national competent authority;

(g) the product is supplied to patients under the supervision of an authorised

healthcare professional;

1b. Member States may temporarily exclude from the scope of this Directive medicinal

products manufactured and supplied exclusively to the armed forces for military or

defence purposes, prepared under the responsibility of the national authority for

military or defense matters and prepared on the basis of national monographs for the

manufacture and quality assessment of these medicinal products.

Without prejudice to Article 30 of [revised Regulation (EC) No 726/2004], Member States

may temporarily authorise the use and distribution of an unauthorised medicinal product in

response to a suspected or confirmed spread of pathogenic agents, toxins, chemical agents or

nuclear radiation any of which could cause harm.

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Member States shall ensure that marketing authorisation holders, manufacturers and

healthcare professionals are not subject to civil or administrative liability for any

consequences resulting from the use of a medicinal product otherwise than for the authorised

therapeutic indications or from the use of an unauthorised medicinal product, where such use

is recommended or required by a competent authority in response to the suspected or

confirmed spread of pathogenic agents, toxins, chemical agents or nuclear radiation any of

which could cause harm. Such provisions shall apply whether or not a national or a

centralised marketing authorisation has been granted.

Liability for defective products, as provided for by [Council Directive 85/374/EEC35 – OP

please replace reference by new instrument COM(2022) 495 when adopted], shall not be

affected by paragraph 3.

Article 4

Definitions

For the purposes of this Directive, the following definitions apply:

(1) ‘medicinal product’ means any substance or combination of substances that fulfils at

least one of the following conditions:

(a) any substance or combination of substances that is presented as having properties

for treating or preventing disease in human beings; or

(b) any substance or combination of substances that may be used in or administered

to human beings with a view to either restoring, correcting or modifying

physiological functions by exerting a pharmacological, immunological or

metabolic action, or to making a medical diagnosis;

Council Directive 85/374/EEC of 25 July 1985 on the approximation of the laws, regulations and
administrative provisions of the Member States, concerning liability for defective products (OJ L 210,
7.8.1985, p. 29).

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(2) ‘substance’ means any matter irrespective of origin, which may be:

(a) human, e.g. tissues and cells, human blood, human secretions and human blood

products;

(b) animal, e.g. whole animals, animal organs and parts thereof, animal tissues and

cells, animal secretions, toxins, extracts, animal blood and animal blood products;

extracts;

(d) chemical, e.g. elements, naturally occurring chemical materials and chemical

products obtained by chemical change or synthesis;

(e) micro-organisms, e.g. bacteria, viruses and protozoa;

(f)

fungi, including micro-fungi (yeast);

(3) ‘active substance’ means any substance or mixture of substances intended to be used in

the manufacture of a medicinal product and that, when used in its production, becomes

an active ingredient of that product intended to exert a pharmacological, immunological

or metabolic action with a view to restoring, correcting or modifying physiological

functions or to make a medical diagnosis;

(4) ‘starting material’ means any material from which an active substance is manufactured

or extracted;

(4a) ‘intermediate product’ means any partly processed material which must undergo

further manufacturing steps before it becomes a bulk medicinal product or

finished medicinal product;

(5) ‘excipient’ means any ingredient of a medicinal product other than the active substance;

(6) ‘functional excipient’ means an excipient that contributes to or enhances the

performance of a medicinal product or performs an action ancillary to that of the active

substance but does not have a therapeutic contribution on its own;

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(7) ‘advanced therapy medicinal product’ means advanced therapy medicinal product as

defined in Article 2(1), point (a), of Regulation (EC) No 1394/2007;

(8) ‘allergen medicinal product’ means any medicinal product that is intended to identify or

induce a specific acquired alteration in the immunological response to an allergen;

(9) ‘competent authorities’ means the Agency and the competent authorities of the

Members States;

(10) ‘Agency’ means the European Medicines Agency;

(11) ‘non-clinical’ means a study or a test conducted in vitro, in silico, or in chemico, or a

non-human in vivo test related to the investigation of the safety and efficacy of a

medicinal product. Such test may include simple and complex human cell-based assays,

microphysiological systems including organ-on-chip, computer modelling, other non-

human or human biology-based test methods, and animal-based tests;

(12) ‘reference medicinal product’ means a medicinal product that is or has been authorised

by a Member State or by the Commission in the Union under Article 5, in accordance

with Article 6;

(13) ‘generic medicinal product’ means a medicinal product that has the same qualitative and

quantitative composition in active substances and the same pharmaceutical form as the

reference medicinal product;

(14) ‘biological medicinal product’ means a medicinal product, the active substance of which

is produced by or extracted from a biological source and which due to its complexity, its

characterisation and the determination of its quality may require a combination of

physico-chemical-biological testing, together with its control strategy;

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(14a) ‘biosimilar medicinal product’ means a biological medicinal product that is similar

to a reference medicinal product and has the same strength, pharmaceutical form,

route of administration

(15) ‘letter of access’ means an original document, signed by the owner of the data or its

representative, that states that the data may be used for the benefit of a third party by a

competent authority or the Commission for the purposes of this Directive;

(16) ‘fixed dose combination medicinal product’ means a medicinal product consisting of a

combination of active substances intended to be placed on the market as a single

pharmaceutical form;

(17) ‘multi-medicinal product package’ means a package that contains more than one

medicinal product under a single invented name and intended to be used in a medical

treatment where the individual medicinal products in the package are for medical

purposes simultaneously or sequentially administered;

(18) ‘radiopharmaceutical’ means any medicinal product that, when ready for use, contains

one or more radionuclides (radioactive isotopes) included for a medicinal purpose;

(19) ‘radionuclide generator’ means any system incorporating a fixed parent radionuclide

from which is produced a daughter radionuclide which is to be obtained by elution or by

any other method and used in a radiopharmaceutical;

(20) ‘kit for radiopharmaceutical preparation’ means any preparation to be reconstituted

or combined with radionuclides in the final radiopharmaceutical, usually prior to its

administration;

(21) ‘radionuclide precursor’ means any other radionuclide produced for the radio-labelling

of another substance prior to administration;

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(22) ‘antimicrobial’ means any medicinal product with a direct action on micro-organisms

used for treatment or prevention of infections or infectious diseases, including

antibiotics, antivirals and, antifungals and antiprotozoals;

(23) ‘integral combination of a medicinal product with a medical device’ means a

combination of a medicinal product with a medical device, as defined by Regulation

(EU) 2017/745, and where:

(a) the two form an integral product and where the action of the medicinal product is

principal and not ancillary to that of the medical device, or

(b) the medicinal product is intended to be administered by the medical device and

the two are placed on the market in such a way that they form a single integral

product that is intended exclusively for use in the given combination and where

the medical device is not reusable.

(24) ‘combined advanced therapy medicinal products’ means a product as defined in Article

2 of Regulation (EC) No 1394/2007, including when a gene therapy medicinal product

is part of the combined advanced therapy medicinal product;

(25) ‘medicinal product in exclusive use with a medical device’ means a medicinal product

presented in a package with a medical device or to be used with a specific medical

device, as defined by Regulation (EU) 2017/745, or with an in-vitro diagnostic

medical device as defined by Regulation (EU) 2017/746, and referenced in the

summary of product characteristics;

(26) ‘combination of a medicinal product with a product other than a medical device’ means

a combination of a medicinal product with a product other than a medical device (as

defined by Regulation (EU) 2017/745) and where the two are intended for use in the

given combination in accordance with the summary of product characteristics;

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(27) ‘immunological medicinal product’ means:

(a) any vaccine, or allergen medicinal product, or any other medicinal product

eliciting an active and specific immune response;

(b) any medicinal product consisting of toxins or, serums, polyclonal or monoclonal

antibodies or other immunoglobulins and used to produce passive immunity or

to diagnose the state of immunity;

(28) 'vaccine’ means any medicinal product that is intended to elicit an active and specific

immune response for prevention, including post exposure prophylaxis, and for treatment

of diseases caused by an infectious agent;

(29) ‘gene therapy medicinal product’ means a medicinal product, except vaccines against

infectious diseases, that contains or consists of:

(a) a substance or a combination of substances intended to edit the host genome in a

sequence-specific manner or that contain or consists of cells subjected to such

modification; or

(b) a recombinant or synthetic nucleic acid used in or administered to human beings

with a view to regulating, replacing or adding a genetic sequence that mediates its

effect by transcription or translation of the transferred genetic materials or that

contain or consists of cells subjected to these modifications;

(30) ‘somatic cell therapy medicinal product’ means a biological medicinal product that has

the following characteristics:

(a) contains or consists of cells or tissues that have been subject to substantial

manipulation so that biological characteristics, physiological functions or

structural properties relevant for the intended clinical use have been altered, or of

cells or tissues that are not intended to be used for the same essential function(s)

in the recipient and the donor;

(b) is presented as having properties for, or is used in or administered to human

beings with a view to treating, preventing or diagnosing a disease through the

pharmacological, immunological or metabolic action of its cells or tissues.

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For the purposes of point (a), the manipulations listed in Annex I to Regulation (EC) No

1394/2007, in particular, shall not be considered as substantial manipulations.

(31) ‘SoHO-derived medicinal product other than ATMPs’ means any medicinal product

containing, consisting of or deriving from a substance of human origin (SoHO), as

defined in Regulation [SoHO Regulation], other than tissues and cells, that is of

standardised consistency and is prepared by:

(a) a method involving an industrial process which includes pooling of donations; or

(b) a process that extracts an active ingredient from the substance of human origin or

transforms the substance of human origin by changing its inherent properties;

(32) ‘risk management plan’ means a detailed description of the risk management system;

(33) ‘environmental risk assessment’ means the evaluation of the risks to the environment, or

risks to public health, posed by the release of the medicinal product in the environment

from following the use and disposal of the medicinal product and the identification of

risk prevention, limitation and mitigation measures. For medicinal product with an

antimicrobials mode of action, the ERA also encompasses an evaluation of the risk for

antimicrobial resistance selection in the environment due to the manufacturing, use and

disposal of that medicinal product;

(34) ‘antimicrobial resistance’ means the ability of a micro-organism to survive or to grow in

the presence of a concentration of an antimicrobial agent that is usually sufficient to

inhibit or kill that micro-organism;

(35) ‘risks related to use of the medicinal product’ means any risk:

(a) relating to the quality, safety or efficacy of the medicinal product as regards

patients' health or public health;

(b) of undesirable effects on the environment posed by the medicinal product;

in the environment including anti-microbial resistance;

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(36) ‘active substance master file’ means a document that contains a detailed description of

the manufacturing process, quality control during manufacture and process validation

prepared in a separate document by the manufacturer of the active substance;

(37) ‘paediatric investigation plan’ means a research and development programme aimed at

ensuring that the necessary data are generated determining the conditions in which a

medicinal product may be authorised to treat the paediatric population;

(38) ‘paediatric population’ means that part of the population aged between birth and under

18 years;

(39) ‘medicinal prescription’ means any medicinal prescription issued by a professional

person qualified to do so;

(40) ‘abuse of medicinal products’ means persistent or sporadic, intentional excessive use of

medicinal products that is accompanied by harmful physical or psychological effects;

(41) ‘benefit-risk balance’ means an evaluation of the positive therapeutic effects of the

medicinal product in relation to the risks referred to in point (35), subpoint (a);

(42) ‘marketing authorisation holder representative’ means the person, commonly known as

local representative, designated by the marketing authorisation holder to represent the

marketing authorisation holder in the Member State concerned;

(43) ‘package leaflet’ means information for the user that accompanies the medicinal

product;

(44) ‘outer packaging’ means the packaging into which is placed the immediate packaging;

(45) ‘immediate packaging’ means the container or other form of packaging immediately in

contact with the medicinal product;

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(46) ‘labelling’ means information on the immediate packaging or the outer packaging;

(47) ‘name of the medicinal product’ means the name, which may be either an invented

name not liable to confusion with the common name, or a common or scientific name

accompanied by a trademark or by the name of the marketing authorisation holder;

(48) ‘common name’ means the international non-proprietary name recommended by the

World Health Organization for an active substance;

(49) ‘strength of the medicinal product’ means the content of the active substances in a

medicinal product, expressed quantitatively per dosage unit, per unit of volume or per

unit of weight according to the dosage form;

(50) ‘falsified medicinal product’ means any medicinal product with a false representation

of:

(a) its identity, including its packaging and labelling, its name or its composition as

regards any of the ingredients including excipients or the strength of those

ingredients;

(b) its source, including its manufacturer, its country of manufacturing, its country of

origin or its marketing authorisation holder; or

channels used;

This definition does not include unintentional quality defects and is without prejudice to

infringements of intellectual property rights.

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(51) ‘public health emergency’ means a public health emergency recognised at Union level

by the Commission under Article 23(1) of Regulation (EU) 2022/2371 of the European

Parliament and of the Council36;

(52) ‘entity not engaged in an economic activity’ means any legal or natural person that is not

engaged in an economic activity and that:

(a) is not profit making an undertaking or controlled by an undertaking; and,

(b) is not owned or controlled directly or indirectly by any undertaking or has

not concluded any agreements with any undertaking concerning sponsorship or

participation to the medicinal product development;

(53) ‘micro, small and medium-sized enterprises’ means micro, small and medium-sized

enterprises as defined in Article 2 of Commission Recommendation 2003/361/EC37;

(54) ‘variation’ or ‘variation of the terms of a marketing authorisation’ means any

amendment to:

(a) the contents of the particulars and documents referred to in Article 6(2), Articles 9

to 14 and Article 62, Annex I and Annex II thereto and Article 6 of the [revised

Regulation (EC) No 726/2004]; or

(b) the terms of the decision granting the marketing authorisation for a medicinal

product, including the summary of product characteristics and any conditions,

obligations, or restrictions affecting the marketing authorisation, or changes to the

labelling or the package leaflet related to changes to the summary of product

characteristics;

Regulation (EU) 2022/2371 of the European Parliament and of the Council of 23 November 2022 on
serious cross-border threats to health and repealing Decision No 1082/2013/EU (OJ L 314, 6.12.2022,
p. 26).

Commission Recommendation of 6 May 2003 concerning the definition of micro, small and medium-
sized enterprises (OJ L 124, 20.5.2003, p. 36).

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(55) ‘post-authorisation safety study’ means any study relating to an authorised medicinal

product conducted with the aim of identifying, characterising or quantifying a safety

hazard, confirming the safety profile of the medicinal product, or of measuring the

effectiveness of risk management measures;

(56) ‘pharmacovigilance system’ means a system used by the marketing authorisation holder

and by Member States to fulfil the tasks and responsibilities set out in Chapter IX and

designed to monitor the safety of authorised medicinal products and detect any change

to their benefit-risk balance;

(57) ‘pharmacovigilance system master file’ means a detailed description of the

pharmacovigilance system used by the marketing authorisation holder with respect to

one or more authorised medicinal products;

(58) ‘risk management system’ means a set of pharmacovigilance activities and interventions

designed to identify, characterise, prevent or minimise risks relating to a medicinal

product, including the assessment of the effectiveness of those activities and

interventions;

(59) ‘adverse reaction’ means a response to a medicinal product that is noxious and

unintended;

(60) ‘serious adverse reaction’ means an adverse reaction that results in death, is life-

threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or is a congenital anomaly or

a birth defect;

(61) ‘unexpected adverse reaction’ means an adverse reaction, the nature, severity or

outcome of which is not consistent with the summary of product characteristics;

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(62) ‘homeopathic medicinal product’ means a medicinal product prepared from

homeopathic stocks in accordance with a homeopathic manufacturing procedure

described by the European Pharmacopoeia or, in the absence thereof, by the

pharmacopoeias currently used officially in the Member States;

(63) ‘traditional herbal medicinal product’ means a herbal medicinal product that fulfils the

conditions laid down in Article 134(1);

(64) ‘herbal medicinal product’ means any medicinal product, exclusively containing as

active ingredients one or more herbal substances or one or more herbal preparations, or

one or more such herbal substances in combination with one or more herbal

preparations;

(65) ‘herbal substances’ means all mainly whole, fragmented or cut plants, plant parts, algae,

fungi, lichen in an unprocessed, usually dried or fresh form, and certain exudates that

have not been subjected to a specific treatment are also considered to be herbal

substances. Herbal substances are precisely defined by the plant part used and the

botanical name according to the binomial system (genus, species, variety and author);

(66) ‘herbal preparations’ means preparations obtained by subjecting herbal substances to

treatments such as extraction, distillation, expression, fractionation, purification,

concentration or fermentation including comminuted or powdered herbal substances,

tinctures, extracts, essential oils, expressed juices and processed exudates;

(67) ‘corresponding traditional herbal medicinal product’ means a traditonal herbal

medicinal product with the same active substances, irrespective of the excipients used,

the same or similar intended purpose, equivalent strength and posology and the same or

similar route of administration as the traditional herbal medicinal product applied for;

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(67a) ’manufacture of medicinal products’ means any total or partial operation as part

of the process of bringing the active substance(s) and excipient(s) to a medicinal

product, including but not limited to processing, filling, sterilisation, assembly,

immediate and outer packaging, and repackaging, storage, quality control testing,

and release of the medicinal product;

(67b) ‘decentralised manufacturing’ means the manufacturing and testing activities for

medicinal products that rely on the existence of a central site that ensures

supervision and control of one or several decentralised sites where parts of the

manufacturing take place and which is located in sufficient proximity to patients;

(67c) ‘manufacture of active substances’ used in the manufacturing process of a

medicinal product’ means any total or partial operation of receipt of materials,

production, packaging, repackaging, labelling, relabelling, quality control or

release of active substances, and the related controls;

(68) ‘wholesale distribution of medicinal products’ means all activities, consisting of

procuring, holding, supplying or exporting medicinal products, whether for profit or not,

apart from supplying medicinal products to the public. Such activities are carried out

with manufacturers or their depositories, importers, other wholesale distributors or with

pharmacists and persons authorised or entitled to supply medicinal products to the

public in the Member State concerned;

(69) ‘brokering of medicinal products’ means all activities in relation to the sale or purchase

of medicinal products, except for wholesale distribution, that do not include physical

handling and that consist of negotiating independently and on behalf of another legal or

natural person;

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(70) ‘public service obligation’ means to guarantee permanently an adequate range of

medicinal products to meet the requirements of a specific geographical area and to

deliver the supplies requested within a very short time over the whole of the area in

question.

The Commission is empowered to adopt delegated acts in accordance with Article 215 to

amend the definitions in paragraph 1, points (2) to (6), (8), (14), (16) to (31), in the light of

technical and scientific progress and taking into account definitions agreed at Union and

international level without extending the scope of the definitions.

Chapter II

Application requirements for national and centralised marketing

authorisations

Section 1

General provisions

Article 5

Marketing authorisations

A medicinal product shall be placed on the market of a Member State only when a marketing

authorisation has been granted by the competent authorities of a Member State in accordance

with Chapter III (‘national marketing authorisation’) or a marketing authorisation has been

granted in accordance with [revised Regulation (EC) No 726/2004] (‘centralised marketing

authorisation’).

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When an initial marketing authorisation has been granted in accordance with paragraph 1, any

development concerning the medicinal product covered by the authorisation such as

additional therapeutic indication, strengths, pharmaceutical forms, administration routes,

presentations, as well as any variations of the marketing authorisation shall also be granted an

authorisation in accordance with paragraph 1 or be included in the initial marketing

authorisation. All those marketing authorisations shall be considered as belonging to the same

global marketing authorisation, in particular for the purpose of the marketing authorisations

applications under Articles 9 to 12, including as regards the expiry of the regulatory data

protection period for applications using a reference medicinal product.

Article 6

General requirements for marketing authorisation applications

In order to obtain a marketing authorisation, an electronic marketing authorisation application

shall be submitted to the competent authority concerned in a common format. The Agency

shall make available such format after consultation with the Member States.

The marketing authorisation application shall include the particulars and documentation listed

in Annex I, submitted in accordance with Annex II.

The documents and information concerning the results of the pharmaceutical and non-clinical

tests and the clinical studies referred to in Annex I shall be accompanied by detailed

summaries in accordance with Article 7 and, when requested by the competent authority,

supportive raw data.

The risk management system referred to in Annex I shall be proportionate to the identified

risks and the potential risks of the medicinal product, and the need for post-authorisation

safety data.

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The marketing authorisation application for a medicinal product that is not authorised in the

Union at the time of entry into force of this Directive and for new therapeutic indications,

including paediatric indications, new pharmaceutical forms, new strengths and new routes of

administration of authorised medicinal products which are protected either by a

supplementary protection certificate under [Regulation (EC) No 469/2009 - OP please replace

reference by new instrument when adopted], or by a patent which qualifies for the granting of

the supplementary protection certificate, shall include one of the following:

(a) the results of all studies performed and details of all information collected in

compliance with an agreed paediatric investigation plan;

(b) a decision of the Agency granting a product-specific waiver pursuant to Article 75(1) of

[revised Regulation No (EC) 726/2004];

Regulation No (EC) 726/2004];

(d) a decision of the Agency granting a deferral pursuant to Article 81 of [revised

Regulation No (EC) 726/2004];

(e) a decision of the Agency taken in consultation with the Commission pursuant to Article

83 of [revised Regulation No (EC) 726/2004] to temporarily derogate from the

provision referred to in points (a) to (d) above in case of health emergencies.

The documents submitted under points (a) to (d) shall, cumulatively, cover all subsets of the

paediatric population.

The provisions of paragraph 5 shall not apply to medicinal products authorised under Articles

9, 11, 13, Articles 125 to 141 and medicinal products authorised under Articles 10 and 12

which are not protected either by a supplementary protection certificate under [Regulation

(EC) No 469/2009 - OP please replace reference by new instrument when adopted], or by a

patent which qualifies for the granting of the supplementary protection certificate.

The marketing authorisation applicant shall demonstrate that the principle of replacement,

reduction and refinement of animal testing for scientific purposes has been applied in

compliance with Directive 2010/63/EU with regard to any animal study conducted in support

of the application.

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The marketing authorisation applicant shall not carry out animal testing in case scientifically

satisfactory non-animal testing methods are available.

Article 7

Expert verification

The marketing authorisation applicant shall ensure that the detailed summaries referred to in

Article 6(3) have been drawn up and signed by experts with the necessary technical or

professional qualifications before they are submitted to the competent authorities. The

technical or professional qualifications of the experts shall be set out in a brief curriculum

vitae.

The experts referred to in paragraph 1 shall justify any use made of scientific literature under

Article 13 in accordance with the requirements set out in Annex II.

Article 8

Medicinal products manufactured outside the Union

Member States shall take all appropriate measures to ensure that:

(a) the competent authorities of the Member States verify that manufacturers and importers of

medicinal products coming from third countries are able to carry out manufacture in

compliance with the particulars supplied pursuant to Annex I, or to and carry out controls

according to the methods described in the particulars accompanying the application in

accordance with Annex I;

(b) the competent authorities of the Member States may allow manufacturers and importers of

medicinal products coming from third countries, in justifiable cases, to have certain stages of

manufacture or certain of the controls referred to in point (a) carried out by third parties; in

such cases, the verifications by the competent authorities of the Member States shall also be

made in the establishment designated.

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Section 2

Specific requirements for abridged, bibliographic or consent based applications

for marketing authorisation

Article 9

Applications concerning generic medicinal products

By way of derogation from Article 6(2), the applicant for a marketing authorisation for a

generic medicinal product shall not be required to provide to the competent authorities the

results of non-clinical tests and of clinical studies if equivalence of the generic medicinal

product with the reference medicinal product is demonstrated.

For the purpose of demonstrating the equivalence as referred to in paragraph 1, the applicant

shall submit to the competent authorities equivalence studies, or a justification as to why such

studies were not performed, and demonstrate that the generic medicinal product meets the

relevant criteria set out in the appropriate detailed guidelines.

Paragraph 1 shall also apply if the reference medicinal product has not been authorised in the

Member State in which the application for the generic medicinal product is submitted. In this

case, the applicant shall indicate in the application the name of the Member State in which the

reference medicinal product is or has been authorised. At the request of the competent

authority of the Member State in which the application is submitted, the competent authority

of the other Member State shall transmit within a period of one month a confirmation that the

reference medicinal product is or has been authorised together with the full composition of the

reference medicinal product and if necessary, any other relevant documentation.

The various immediate-release oral pharmaceutical forms shall be considered to be the same

pharmaceutical form.

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The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an

active substance shall be considered to be the same active substance, unless they differ

significantly in properties with regard to safety or efficacy. In those cases, the applicant shall

submit additional information to demonstrate that the different salts, esters, ethers, isomers,

mixtures of isomers, complexes or derivatives of an active substance do not differ

significantly in respect of those properties.

Where there is a significant difference in properties as referred to in paragraph 4, the applicant

shall submit additional information in order to prove the safety or efficacy of the different

salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of the authorised

active substance of the reference medicinal product in an application under Article 10.

Article 10

Applications concerning hybrid medicinal products

In cases where the medicinal product does not fall within the definition of a generic medicinal

product or has changes in strength, pharmaceutical form, route of administration or therapeutic

indications, compared to the reference medicinal product, the results of the appropriate non-clinical

tests or clinical studies shall be provided to the competent authorities to the extent necessary to

establish a scientific bridge to the data relied upon in the marketing authorisation for the reference

medicinal product, and to demonstrate the safety and efficacy profile of the hybrid medicinal

product.

Article 11

Applications concerning biosimilar medicinal products

For a biological medicinal product that is similar to a reference biological medicinal product

(‘biosimilar medicinal product’), the results of appropriate comparability tests and studies shall be

provided to the competent authorities. The type and quantity of supplementary data to be provided

must comply with the relevant criteria stated in Annex II and the related detailed guidelines. The

results of other tests and studies from the reference medicinal product's dossier shall not be

provided.

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Article 12

Applications concerning bio-hybrid medicinal products

In cases where a biosimilarthe biological medicinal product does not fall within the definition of

a biosimilar medicinal product or has changes in strength, pharmaceutical form, route of

administration or therapeutic indications, compared to the reference biological medicinal product

(‘bio-hybrid’), the results of the appropriate non-clinical tests or clinical studies shall be provided to

the competent authorities to the extent necessary to establish a scientific bridge to the data relied

upon in the marketing authorisation for the reference biological medicinal product, and to

demonstrate the safety or and efficacy profile of the biosimilar bio-hybrid medicinal product.

Article 13

Applications based on bibliographic data

In cases where, at the time of submission of the marketing authorisation application, no

reference medicinal product is or has been authorised or if a reference medicinal product has

been authorised but is not available on the market within the Union for the active substance of

the medicinal product concerned, the applicant shall, by way of derogation from Article 6(2), not be

required to provide the results of non-clinical tests or clinical studies if the applicant can

demonstrate that the active substances of the medicinal product have been in well-established

medicinal use within the Union for the same therapeutic use and route of administration and for at

least ten years, with recognised efficacy and an acceptable level of safety in terms of the conditions

set out in Annex II. In that event, the test and trial results shall be replaced by appropriate

bibliographic data in the form of scientific literature, and the applicant shall establish a scientific

bridge between the bibliographic data and the medicinal product concerned.

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Article 14

Applications based on consent

Following the granting of a marketing authorisation, the marketing authorisation holder may, by

letter of access, allow use to be made of all documentation referred to in Article 6(2) with a view to

for the purpose of examining subsequent applications relating to other medicinal products

possessing the same qualitative and quantitative composition in terms of active substances and the

same pharmaceutical form.

Section 3

Specific requirements for applications for certain categories of medicinal

products

Article 15

Fixed dose combination medicinal product, platform technologies marketing authorisations and

multi-medicinal product packages

Where justified for therapeutic clinical purposes, a marketing authorisation may be granted

for a fixed dose combination medicinal product.

Where justified for therapeutic clinical purposes, a marketing authorisation may, in

exceptional circumstances, be granted for a medicinal product comprised of a fixed

component and a variable component that is pre-defined in order to, where appropriate, target

different variants of an infectious agent or, where necessary, to tailor the medicinal product to

characteristics of an individual patient or a group of patients (‘platform technology’)

(‘platform marketing authorisation’).

An applicant that intends to submit an application for a marketing authorisation for such a

medicinal product shall seek, in advance, the agreement concerning the submission of such

application by the competent authority concerned.

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Where justified for public health reasons and when the active substances cannot be combined

within a fixed dose combination medicinal product, a marketing authorisation may, in

exceptional circumstances, be granted to a multi-medicinal product package.

An applicant that intends to submit a an application for a marketing authorisation for such a

medicinal product shall seek, in advance, the agreement concerning the submission of such

application by the competent authority concerned.

Article 16

Radiopharmaceuticals

A marketing authorisation shall be required for radionuclide generators, kits for

radiopharmaceutical preparation, and radionuclide precursors, unless they are used as

starting material, active substance or intermediate of radiopharmaceuticals covered by a

marketing authorisation under Article 5(1). Member States may, in justified cases, regulate

substance-related exemptions from the authorisation requirement for radionuclide

precursors for diagnostic radioactive medicinal products, if this is necessary to secure an

adequate supply of radionuclides throughout the facilities for nuclear medicine and if

the safety and quality profile for the radionuclide precursor is established and assured.

A marketing authorisation shall not be required for a radiopharmaceutical prepared at the time

of use by a person or by an establishment authorised, according to national legislation, to use

such radiopharmaceutical in an approved healthcare establishment exclusively from

authorised radionuclide generators, kits for radiopharmaceutical preparation or

radionuclide precursors in accordance with the manufacturer's instructions in accordance

with the in the summary of product characteristics.

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Article 17

Antimicrobials

Where the application for a marketing authorisation concerns an antimicrobial, the application

shall, in addition to the information referred to in Article 6, contain the following:

(a) an antimicrobial stewardship plan as referred to in Annex I;

(b) a description of the special information requirements outlined in Article 69 and listed in

Annex I.

The competent authority may impose obligations on the marketing authorisation holder if it

finds the risk mitigation measures contained in the antimicrobial stewardship plan

unsatisfactory.

The marketing authorisation holder shall ensure, where the pack is intended for direct

dispensing to patients, that the pack size of the antimicrobial corresponds to the usual

posology and duration of treatment.

Article 18

Integral combinations of medicinal products and medical devices

For integral combinations of a medicinal product and a medical device the marketing

authorisation applicant shall submit data establishing the safe and effective use of the integral

combination of the medicinal product and the medical device.

As part of the assessment, in accordance with Article 29, of the integral combination of a

medicinal product and a medical device the competent authorities shall assess the benefit-risk

balance of the integral combination of a medicinal product and a medical device, taking into

account the suitability of the use of the medicinal product together with the medical device.

The relevant general safety and performance requirements set out in Annex I of Regulation

(EU) 2017/745 shall apply as far as the safety and performance of the medical device part of

the integral combination of a medicinal product with a medical device are concerned.

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The application for a marketing authorisation for an integral combination of a medicinal

product with a medical device shall include the documentation supporting the compliance of

the medical device part with the general safety and performance requirements as referred to in

paragraph 2 in accordance with Annex II, including, the results of the conformity

assessment of the device part with the general safety and performance requirements of

Regulaton (EU) 2017/745 or an opinion on the conformity of the device part with the

general safety and performance requirements of Regulation (EU) 2017/745 by a notified

bodywhere relevant, the conformity assessment report by a notified body.

In its evaluation of the integral combination of a medicinal product with a medical device

concerned, the competent authorities shall recognise the results of the assessment of

compliance of the medical device part of that integral combination with the general safety and

performance requirements in accordance with Annex I of Regulation (EU) 2017/745

including, where relevant, the results of the assessment by a notified body.

The marketing authorisation applicant shall, upon request from the competent authority,

submit any additional information related to the medical device and that is relevant for the

benefit-risk balance assessment of the integral combination of a medicinal product with a

medical device referred to in paragraph 1.

Article 19

Medicinal products in exclusive use with medical devices or in-vitro diagnostic medical devices

For medicinal products in exclusive use with a medical device or in-vitro diagnostic medical

device the marketing authorisation applicant shall submit data establishing the safe and

effective use of the medicinal product taking into account its use with the medical device.

As part of the assessment, in accordance with Article 29, of the medicinal product referred to

in the first subparagraph, the competent authorities shall assess the benefit-risk balance of the

medicinal product taking into account the use of the medicinal product together with the

medical device or in-vitro diagnostic medical device.

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For medicinal products in exclusive use with a medical device or in-vitro diagnostic medical

device the medical device or in-vitro diagnostic medical device shall meet the requirements

set out in Regulation (EU) 2017/745 or Regulation (EU) 2017/746, as applicable.

The application for a marketing authorisation for a medicinal product in exclusive use with a

medical device or in-vitro diagnostic medical device shall include the documentation

supporting the compliance of the medical device or in-vitro diagnostic medical device with

the general safety and performance requirements as referred to in paragraph 2 in accordance

with Annex II, including, where relevant, the results of the conformity assessment or the

conformity assessment report by a notified body.

In its evaluation of the medicinal product referred to in paragraph 1 the competent authority

shall recognise the results of the assessment of compliance of the medical device or in-vitro

diagnostic medical device concerned with the general safety and performance requirements

in accordance with Annex I of Regulation (EU) 2017/745 or (EU) 2017/746, as applicable,

including, where relevant, the results of the assessment by a notified body.

The marketing authorisation applicant shall, upon request from the competent authority,

submit any additional information related to the medical device and that is relevant for the

benefit-risk balance assessment of the medicinal product referred to in paragraph 1, taking

into account the use of the medicinal product with the medical device.

If the action of the medicinal product is not ancillary to that of the medical device, the

medicinal product shall comply with the requirements of this Directive and of the [revised

Regulation (EC) No 726/2004], taking into account its use with the medical device, without

prejudice to the specific requirements of the Regulation (EU) 2017/745.

In this case, the marketing authorisation applicant shall, upon request from the competent

authorities, submit any additional information related to the medical device, taking into

account its use with the medicinal product and that is relevant for the post-authorisation

monitoring of the medicinal product, without prejudice to the specific requirements of the

[revised Regulation (EC) No 726/2004].

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Article 20

Combinations of medicinal products with products other than medical devices

For combinations of a medicinal product with a product other than a medical device, the

marketing authorisation applicant shall submit data establishing the safe and effective use of

the combination of the medicinal product and the other product.

As part of the assessment, in accordance with Article 29, of the combination of a medicinal

product with a product other than a medical device the competent authority shall assess the

benefit-risk balance of the combination of a medicinal product and a product other than a

medical device, taking into account the use of the medicinal product together with the other

product.

The marketing authorisation applicant shall, upon request from the competent authority

submit any additional information related to the product other than medical devices and that is

relevant for the benefit-risk balance assessment of the combination of medicinal products with

the product other than medical devices, taking into account the suitability of the use of the

medicinal product with the product referred to in paragraph 1.

The competent authority may request an opinion from the authority competent for the

supervision of the product other than a medical device.

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Section 4

Specific dossier requirements

Article 21

Risk management plan

The applicant of a marketing authorisation for a medicinal product referred to in Articles 9

and 11 shall not be required to submit a risk management plan and a summary thereof,

provided that no additional risk minimisation measures exist for the reference medicinal

product and provided that the marketing authorisation for the reference medicinal product has

not been withdrawn prior to the submission of the application.

The risk management plan for medicinal products referred to in Articles 10 and 12 shall

be limited to the differences between this medicinal product and the reference medicinal

product, provided that no additional risk minimisation measures exist for the reference

medicinal product and provided that the marketing authorisation for the reference

medicinal product has not been withdrawn prior to the submission of the application.

Article 22

Environmental risk assessment and other environmental information

When preparing the environmental risk assessment (‘ERA’) to be submitted pursuant to

Article 6(2), the applicant shall take into account the scientific guidelines on the

environmental risk assessment of medicinal products for human use as referred to in

paragraph 56, or provide the reasons for any divergence from the scientific guidelines to the

Agency or, as appropriate to the competent authority of the Member State concerned, in a

timely manner. Where available, the applicant shall take into account existing ERAs

performed under other Union legislation.

The ERA shall indicate whether the medicinal product or any of its ingredients or other

constituents is one of the following substances according to the criteria of Annex I to the

Regulation (EC) No 1272/2008:

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(a) persistent, bioaccumulative and toxic (PBT);

(b) very persistent and very bioaccumulative (vPvB);

or are endocrine active agents disruptors.

The applicant shall also include in the ERA risk mitigation measures to avoid or where it is

not possible, limit emissions to air, water and soil of ingredients and constituents of

medicinal products listed as of pollutants listed in Directive 2000/60/EC, Directive

2006/118/EC, Directive 2008/105/EC and Directive 2010/75/EU. The applicant shall provide

detailed explanation that the proposed mitigation measures are appropriate and sufficient to

address the identified risks to the environment.

The ERA for antimicrobials shall include an evaluation of the risk for antimicrobial resistance

selection in the environment due to the entire manufacturing supply chain inside and outside

the Union, use and disposal of the antimicrobial taking into account, where relevant, the

existing international standards that have established predicted no effect concentration

(PNECs) specific for antibiotics.

The Agency shall draw up scientific guidelines in accordance with Article 138 of [revised

Regulation No (EC) 726/2004], to specify technical details regarding the ERA requirements

for medicinal products for human use. Where appropriate, the Agency shall consult the

European Chemical Agency (ECHA), the European Food Safety Authority (EFSA) and the

European Environmental Agency (EEA) on the drafting of these scientific guidelines.

The marketing authorisation holder shall update the ERA with new information without

undue delay to the relevant competent authorities, in accordance with Article 90(2), if new

information pertaining to the assessment criteria referred to in Article 29 becomes available

and could lead to a change of the conclusions of the ERA. The update shall include any

relevant information from environmental monitoring, including monitoring under Directive

2000/60/EC, from eco-toxicity studies, from new or updated risk assessments under other

Union legislation, as referred to in paragraph 1, and environmental exposure data.

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For an ERA conducted prior to [OP please insert the date = 18 months after the date of

entering into force of this Directive], the competent authority shall request the marketing

authorisation holder to update the ERA if missing information has been identified for

medicinal products potentially harmful to the environment.

For medicinal products referred to in Articles 9 to 12 and 14 and fixed dose combinations

the applicant may refer to ERA studies conducted for the reference medicinal product or to

ERA studies of any other medicinal product containing the same active substances, when

preparing the ERA.

Article 23

ERA of medicinal products authorised before 30 October 2005

By [OP please insert the date = 30 months after the date of the entry into force of this

Directive] the Agency shall, after consultation with the competent authorities of the Member

States, the European Chemical Agency (ECHA), the European Food Safety Authority (EFSA)

and the European Environmental Agency (EEA), establish a programme for the ERA to be

submitted in accordance with Article 22 of the medicinal products authorised before 30

October 2005 that have not been subject to any ERA and that the Agency has identified as

potentially harmful to the environment in accordance with paragraph 2.

This programme shall be made publicly available by the Agency.

The Agency shall set the scientific criteria for the identification of the medicinal products as

potentially harmful to the environment and for the prioritisation of their ERA, using a risk

based approach. For this task, the Agency may request from marketing authorisation holders

the submission of relevant data or information.

The marketing authorisation holders for medicinal products identified in the programme

referred to in paragraph 1 shall submit the ERA to the Agency. The outcome of the

assessment of the ERA including the data submitted by the marketing authorisation holder

shall be made publicly available by the Agency.

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Where there are several medicinal products identified in the programme referred to in

paragraph 1 that contain the same active substance and that are expected to pose the same

risks to the environment, the competent authorities of the Member States or the Agency shall

encourage the marketing authorisation holders to conduct joint studies for the ERA, to

minimise unnecessary duplication of data and use of animals.

For medicinal products referred to in Articles 9 to 12 and 14 and fixed-dose

combinations, for which the reference medicinal product or the medicinal product

containing the same active substance has been authorised before 30 October 2005, and

which are included in this programme, the ERA shall be submitted after the outcome of

the ERA of such reference medicinal product is made publicly available by the Agency.

Article 24

System of ERA monographs of the ERA data of active substances

The Agency shall, in collaboration with the competent authorities of the Member States, set-

up an active substance based review system of ERA data (‘ERA monographs’) for authorised

medicinal products. An ERA monograph shall include a comprehensive set of physiochemical

data, fate data and effect data based on an assessment of a competent authority.

The setting-up of the system of ERA monographs shall be based on a risk-based prioritisation

of active substances.

In the preparation of the ERA monograph referred to in paragraph 1, the Agency may request

available information, studies and data from competent authorities of the Member States and

from marketing authorisation holders.

The Agency in cooperation with the competent authorities of the Member States shall conduct

a proof-of-concept pilot of ERA monographs to be completed within three years after entering

into force of this Directive.

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The Commission is empowered to adopt delegated acts in accordance with Article 215 and

based on the results of a proof-of-concept pilot referred to in paragraph 4, to supplement this

Directive by specifying the following:

(a) the content and format of ERA monographs;

(b) the procedures for adopting and updating the ERA monographs;

(d) the risk-based prioritisation criteria for the selection and prioritisation referred to in

paragraph 2;

(e) the use of ERA monographs in the context of new marketing authorisation applications

for medicinal products to support their ERA.

Article 25

Active substance master file certificate

Marketing authorisation applicants may, instead of submitting the relevant data on a chemical

active substance of a medicinal product required in accordance with Annex II, rely on an

active substance master file, an active substance master file certificate granted by the Agency

in accordance with this Article (‘active substance master file certificate’) or a certificate

confirming that the quality of the active substance concerned is suitably controlled by the

relevant monograph of the European Pharmacopeia.

Marketing authorisation applicants may only rely on an active substance master file if no

certificate exists on the same active substance master file.

The Agency shall be responsible for the granting of an active substance mater file

certificate. An active substance master file certificate may be granted by the Agency in cases

where the relevant data on the active substance concerned is not already covered by a

monograph of the European Pharmacopeia or by an active substance master file certificate.

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In order to obtain an active substance master file certificate, an application shall be submitted

to the Agency. The applicant for an active substance master file certificate shall demonstrate

that the active substance concerned is not already covered by a monograph of the European

Pharmacopeia or an active substance master file certificate. The Agency shall examine the

application and, in case of a positive outcome, shall grant the certificate that shall be valid

throughout the Union.

The application for an active substance master file certificate may be submitted to the

Agency separately from a marketing authorisation application. In case of centralised

marketing authorisations, the application for an active substance master file certificate may be

submitted as part of the marketing authorisation application for the corresponding medicinal

product.

The Agency shall establish a repository of active substance master files, their assessments

reports and their certificates and ensure that personal data and information of a

commercially confidential nature is protected. The Agency shall ensure that the competent

authorities of the Member State have access to this repository.

The active substance master file and the active substance master file certificate shall cover all

the information required in Annex II on the active substance.

The active substance master file certificate holder shall be the manufacturer of the active

substance.

The active substance master file certificate holder shall keep the active substance master file

up to date with scientific and technological progress and introduce the changes required to

ensure that the active substance is manufactured and controlled in accordance with generally

accepted scientific methods.

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If requested by the Agency, the manufacturer of the substance for which an application for an

active substance master file certificate has been submitted or the active substance master file

certificate holder shall undergo an inspection to verify the information contained in the

application or the active substance master file or their compliance with good manufacturing

practices for active substances referred to in Article 160.

If the manufacturer of an active substance refuses to undergo such an inspection, the Agency

may suspend or terminate the application for an active substance master file certificate.

If the active substance master file certificate holder does not fulfil the obligations set out in

the paragraphs 5 and 6, the Agency may suspend or withdraw the certificate and, the

competent authorities of the Member States may suspend or revoke the marketing

authorisation of a medicinal product relying on that certificate or take measures to prohibit the

supply of the medicinal product relying on that certificate.

The marketing authorisation holder of the medicinal product granted on the basis of an active

substance master file certificate remains responsible and liable for that medicinal product.

The Commission is empowered to adopt delegated acts in accordance with Article 215 to

supplement this Directive by specifying, the following:

(a) the rules governing the content and format of the application for an active substance

master file certificate;

(b) the rules for the submission and examination of an application for an active substance

master file certificate and for the granting of the certificate;

(d) the rules for introducing changes to the active substance master file and the active

substance master file certificate;

(e) the rules on access for competent authorities of the Member States to the active

substance master file and its assessment report;

(f)

the rules on access for marketing authorisation applicants and marketing authorisation

holders relying on an active substance master file certificate to the active substance

master file and to the assessment report.

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Article 26

Additional quality master files

Marketing authorisation applicants may, instead of submitting the relevant data on an active

substance other than a chemical active substance, or on other substances present or used in the

manufacture of a medicinal product, required in accordance with Annex II, rely on an

additional quality master file, an additional quality master file certificate granted by the

Agency in accordance with this Article (‘additional quality master file certificate’), or a

certificate confirming that the quality of that substance is suitably controlled by the relevant

monograph of the European Pharmacopeia.

Marketing authorisation applicants may only rely on an additional quality master file

certificate if no certificate exists on the same additional quality master file.

Article 25, paragraphs 1 to 5, 7 and 8 shall also apply mutadis mutandis to additional quality

master file certification.

2a. The Commission is empowered to adopt delegated acts to identify, in the light of

scientific progress, the substances to which this Article shall apply. A substance shall

only be identified under this paragraph, if the use of additional quality master files is

scientifically justified.

The Commission is empowered to adopt delegated acts in accordance with Article 215 to

supplement this Directive by specifying:

(a) the rules governing the content and format of the application for an active substance

additional quality master file certificate;

(b) additional quality master files for which a certificate may be used in order to provide

specific information on the quality of a substance present or used in the manufacture of

a medicinal product;

quality master file certificates;

(d) the rules for introducing changes to the additional quality master file and the certificate;

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(e) the rules on access for competent authorities of the Member State to the additional

quality master file and its assessment report;

(f)

the rules on access for marketing authorisation applicants and marketing authorisation

holders relying on an additional quality master file certificate to the additional quality

master file and to the assessment report.

If requested by the Agency, the manufacturer of a substance present or used in the

manufacture of a medicinal product for which an application for an additional quality master

file certificate has been submitted or the additional quality master file certificate holder shall

undergo an inspection to verify the information contained in the application or the quality

master file.

If the manufacturer of this substance refuses to undergo such an inspection, the Agency may

suspend or terminate the application for the additional quality master file certificate.

Article 26a

Medicinal products concerned with decentralised manufacturing

When justified by the specific properties of the manufactured medicinal product and

consideration related to the quality, safety and efficacy of a medicinal product, such as

short shelf life, or where proximity to the treated patient or customisation for an

individual patient to their benefit, the marketing authorisation applicant may request

the competent authority to approve the use of a decentralised manufacturing site as

referred to in Chapter XI as part of the manufacturing of the medicinal product

concerned.

The request referred to in paragraph 1 shall be submitted as part of the marketing

authorisation application in accordance with Annex II.

The competent authority shall assess the request referred to in paragraph 1 as part of

the assessment of the marketing authorisation application.

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The competent authority referred to in paragraph 3, shall cooperate with all relevant

regulatory authorities, including with the supervisory authority in charge of the

authorisation of the central site identified in the application. The manufacturing

authorisation of the central site referred to in Article 142 shall be provided as part of the

procedure for a marketing authorisation.

The approval to use decentralised manufacturing shall be included in the terms of the

marketing authorisation.

The approval to use decentralised manufacturing may be withdrawn by the competent

authority, where it concludes that the justification referred to in paragraph 1 is no

longer fulfilled or that the conditions for decentralised manufacturing as referred to in

chapter XI are not complied with. The competent authority shall inform the the

supervisory authority in charge of the authorisation of the central site of such a

circumstance without undue delay.

The marketing authorisation holders making use of decentralised manufacturing shall

provide the competent authority with any new information that might entail an

amendment to the terms of the marketing authorisation as referred to in paragraph 5, in

accordance with Article 90.

The Commission may adopt implementing acts to set out the format and content of the

request and on the application of principles as referred to in paragraph 1.

Article 27

Excipients

The applicant shall provide information on the excipients used in a medicinal product in

accordance with the requirements set out in Annex II.

Excipients shall be examined by the competent authorities as part of the medicinal product.

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Colours shall be used in medicinal products only if they are included in one of the following

lists:

(a) the Union list of authorised food additives in Table 1 in Part B of Annex II to

Regulation (EC) No 1333/2008 and comply with the purity criteria and specifications

laid down in Commission Regulation (EU) No 231/2012;

(b) the list established by the Commission pursuant to paragraph 3.

The Commission may establish a list of colours permitted for use in medicinal products other

than those included in the Union list of authorised food additives.

The Commission shall, where applicable on the basis of an opinion of the Agency, adopt a

decision whether the colour concerned shall be added to list of colours permitted for use in

medicinal products referred to in the first subparagraph.

A colour may be added to the list of colours permitted for use in medicinal products only

where the colour has been removed from the Union list of authorised food additives.

Where relevant, the list of colours permitted for use in medicinal products shall include purity

criteria, specifications or restrictions applicable to the colours included in that list.

The list of colours permitted for use in medicinal products shall be established by way of

implementing acts. Those implementing acts shall be adopted in accordance with the

examination procedure referred to in Article 214(2).

If a colour used in medicinal product is removed from the Union list of authorised food

additives, on the basis of the scientific opinion of the European Food Safety Authority

(‘EFSA’), the Agency shall, on the request of the Commission or on its own initiative,

without undue delay issue a scientific opinion as regards the use of the colour concerned in

medicinal product, taking into account the opinion of the EFSA if relevant. The opinion of the

Agency shall be adopted by the Committee for Medicinal Products for Human Use.

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The Agency without undue delay shall send to the Commission its scientific opinion on the

use of the colour in medicinal product together with a report on the assessment.

The Commission shall, on the basis of the Agency opinion, and without undue delay, decide

whether the colour concerned can be used in medicinal products and, where applicable,

include it in the list of colours permitted for use in medicinal products referred to in paragraph

If a colour has been removed from the Union list of authorised food additives for reasons that

do not require an EFSA opinion, the Commission shall decide on the use of the colour

concerned in medicinal products and, where applicable, include it in the list of colours

permitted for use in medicinal products referred to in paragraph 3. The Commission may, in

such cases, request the opinion from the Agency.

A colour that has been removed from the Union list of authorised food additives can still be

used as a colour in medicinal products until the Commission takes the decision on whether to

include the colour on the list of colours permitted for use in medicinal products in accordance

with paragraph 3.

Paragraphs 2 to 6 shall also apply to colours used in veterinary medicinal products as defined

in Article 4(1) of Regulation (EU) 2019/6 of the European Parliament and of the Council 38.

Paragraph 6 shall not apply to food-producing-animals as defined in Article 4(38) of

Regulation (EU) 2019/6 of the European Parliament and of the Council.”

Regulation (EU) 2019/6 of the European Parliament and of the Council of 11 December 2018 on
veterinary medicinal products and repealing Directive 2001/82/EC.

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Section 5

Adapted dossier requirements

Article 28

Adapted frameworks due to the characteristics or methods inherent to the medicinal product or

category of medicinal products

Medicinal products or category of medicinal products listed in Annex VII shall be subject

to adapted specific scientific or regulatorytechnical requirements (‘adapted framework’)

which are necessary for assessing whether a marketing authorisation as referred to in

Article 5 may be granted for those medicinal products or category due to the

characteristics or methods inherent to the medicinal product or category of medicinal

products,. A medicinal product or category of medicinal products shall be listed in

Annex VII when:

(a) it is not possible to adequately assess the quality, safety and efficacy of the medicinal

product or category of medicinal products by applying the applicable requirements set

out in this Directive, the [revised Regulation (EC) No 726/2004] or Regulation

1394/2007 due to scientific or regulatory technical challenges arising fromrelated to

objective and structural characteristics or methods inherent to the medicinal product

or category of medicinal products; and

(b) the characteristics or methods inherent to the medicinal product or category of

medicinal products positively impact contribute to the quality, safety and efficacy of

the medicinal product or category of medicinal products in an at least equivalent

manner to the standards set out in this Directive [and revised Regulation 726/2004]

or provide a major contribution to patient access to prevention, diagnosis, treatment

or patient care.

The Commission, after having consulted the Agency, The Commission is empowered to

adopt delegated acts in accordance with Article 215 to amend the list of medicinal products

or categories of medicinal products listed in Annex VII in order to take account of

scientific and technical progress.

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The Commission is empowered, after having consulted the Agency, to adopt delegated acts

in accordance with Article 215 to supplement this Directive by to supplement this Directive

by laying down the adapted framework for medicinal products or categories of medicinal

produts listed in Annex VII as well as the technical documentation to be submitted by

the marketing authorisation applicants for the medicinal product or category of

medicinal products for which the adapted framework is laid down.

The adapted framework may entail specific and targeted technical adaptations to the

requirements set out in this Directive and [revised Regulation 726/2004] which are

necessary for the purposes of assessing whether a marketing authorisation referred to in

Article 5 can be granted for a medicinal product or category of medicinal products listed

in Annex VII. The technical adaptations shall be proportionate to the risk and impact

involved and shall be based on objective and scientific considerations. In particular, any

technical adaptation shall ensure equivalent standards of quality, safety and efficacy to

those set out in this Directive and shall be limited to the extent where such adaptations

are proportionate and duly justified by the characteristics or methods inherent to the

medicinal product or category of medicinal products. The technical adaptations shall be

regularly reviewed and evaluated by the Commission.

(a) detailed rules for the marketing authorisation and supervision of the medicinal products

referred to in paragraph 1;

(b) the technical documentation to be submitted by applicants for marketing authorisations

for medicinal products referred to in paragraph 1.

The authorisation of a medicinal product subject to an adapted framework as referred

to in paragraph 3 may be granted only if the benefit-risk balance of the medicinal

product is favourable. The detailed rules referred to in paragraph 3, point (a), shall be

proportionate to the risk and impact involved. These may entail adapted, enhanced, waived or

deferred requirements. Any waiver or deferral shall be limited to the extent strictly necessary,

proportionate and duly justified by the characteristics or methods inherent to the medicinal

product, and shall be regularly reviewed and evaluated. Apart from the detailed rules referred

to in paragraph 3, point (a), all other rules laid out in this Directive shall apply.

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Until the adoption of technical adaptations detailed rules for specific medicinal products or

category of medicinal products listed in Annex VII pursuant to paragraph 3, an application

for a marketing authorisation for that medicinal product may be submitted in accordance with

Article 6(2).

When adopting delegated acts referred to in this Article, the Commission shall take into

account any available information resulting from a regulatory sandbox established in

accordance with Article 115 of the [revised Regulation (EC) No 726/2004].

Chapter III

Procedures for national marketing authorisations

Section 1

General provisions

Article 29

Examination of marketing authorisation application

In order to examine an application submitted in accordance with Articles 6 and 9 to 14, the

competent authority of the Member State:

(a) shall verify whether the particulars and documentations submitted in support of the

application comply with Articles 6 and 9 to 14 (‘validation’), and examine whether the

conditions for issuing a marketing authorisation set out in Articles 43 to 45 are complied

with;

(b) may submit the medicinal product, its starting materials or ingredients and, if need be,

its intermediate products or other constituents, for testing by an Official Medicines

Control Laboratory or a laboratory that a Member State has designated for that purpose

in order to ensure that the control methods employed by the manufacturer of medicinal

products and described in the particulars accompanying the application in accordance

with Annex I are satisfactory;

accompanying the application in respect of the items listed in the Articles 6 and 9 to 14;

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(d) may consider and decide upon additional evidence that is available to the competent

authority of that Member State, independently from the data submitted by the

marketing authorisation applicant and to require changes in the summary of product

characteristics.

(e) may, where appropriate, require the applicant to provide raw data concerning the

pharmaceutical and non-clinical tests and the clinical studies referred to in

Annex I.

Where the competent authority of the Member State avails itself of the option referred to in the

first subparagraph, point (c), the time limits laid down in Article 30 shall be suspended until

such time as the supplementary information required has been provided or for the time allowed

to the applicant for giving oral or written explanations.

Where, in the course of the validation referred to in paragraph 1, point (a), the competent

authority of the Member State considers that the marketing authorisation application is

incomplete, or contains critical deficiencies to the extent that this may prevent the evaluation

of the medicinal product application, it shall inform the applicant accordingly and shall set a

time limit for submitting the missing information and documentation. If the applicant fails to

provide the missing information and documentation within the time limit set, the application

shall be considered to have been withdrawn by the applicant.

3a. Where the competent authority of the Member State avails itself of the option referred to in the

first subparagraph paragraph 1, point (c), the time limits laid down in Article 30 shall be

suspended until such time as the supplementary information required has been provided or for

the time allowed to the applicant for giving oral or written explanations.

In cases where on examination of an application for a marketing authorisation the competent

authority of the Member State considers that the submitted data are not of sufficient quality or

maturity for the completion of the examination of the application, the examination can be

terminated within 90 days of the date of validation of the application.

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Prior to the termination, tThe competent authority of the Member State shall summarise the

deficiencies in writing. On this basis, the competent authority of the Member State shall

inform the applicant accordingly and set a time limit to address the deficiencies. The

application shall be suspended until the applicant addresses the deficiencies. If the applicant

fails to address those deficiencies within the time limit set by the competent authority of the

Member State, the examination shall be terminated and the application shall be considered

as withdrawn.

In case a potential serious risk to public health related to the reference medicinal

product is examined under a specific procedure under this Directive or [revised

Regulation (EC) No 726/2004], the Member States shall suspend the examination of any

marketing authorisation application submitted under Articles 9 to 12 that uses the same

reference medicinal product until the end of the procedure related to the reference

medicinal product.

Where a competent authority of the Member State becomes aware that another

marketing authorisation application for the same medicinal product is being examined

by a competent authority of another Member State it shall refuse to validate the

application and advise the applicant to use the procedure referred to in Articles 34 or

36.

Where the competent authorities of the Member States become aware that another

Member State has authorised a the same medicinal product, they shall refuse to validate

the application unless it was submitted in compliance with the provisions referred to in

Articles 34 or 36.

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Article 30

Duration of examination of marketing authorisation application

Member States shall take all appropriate measures to ensure that the procedure for granting a

marketing authorisation for medicinal products is completed within a maximum of 180 210 days

after the submission of a valid application from the date of validation of a marketing authorisation

application.

Article 31

Types of national marketing authorisation procedures

National marketing authorisations may be granted in accordance with the procedures laid down in

Article 32 (‘purely national marketing authorisation procedure’), Articles 33 and 34 (‘decentralised

procedure for national marketing authorisation’) or Articles 35 and 36 (‘mutual recognition

procedure for national marketing authorisation’).

Section 2

Marketing authorisations valid in a single Member State

Article 32

Purely national marketing authorisation procedure

An application for marketing authorisation according to Article 6(2) under the purely national

marketing authorisation procedure shall be submitted to the competent authority in that

Member State in which the marketing authorisation is applied.

The competent authority in the Member State concerned shall examine the application in

accordance with Articles 29 and 30, prepare an assessment report and grant a marketing

authorisation in accordance with Articles 43 to 45 and applicable national provisions.

A marketing authorisation granted under the purely national marketing authorisation

procedure shall be valid only in the Member State of the competent authority that granted it.

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ection 3

Marketing authorisations valid in several Member States

Article 33

Scope of decentralised procedure for national marketing authorisations

An application for marketing authorisation under the decentralised procedure for national

marketing authorisation in several Member States in respect of the same medicinal product

shall be submitted to the competent authorities in those Member States in which the

marketing authorisation is applied.

The competent authorities in the Member State concerned shall examine the applications in

accordance with Articles 29, 30 and 34 and grant a marketing authorisation in accordance

with Articles 43 to 45.

Where a competent authority of the Member State notes that another marketing authorisation

application for the same medicinal product is being examined by the competent authority in

another Member State, the competent authorities of the Member States concerned shall

decline to examine the application and shall advise the applicant that the provisions referred

to in Articles 35 and 36 apply.

Where the competent authorities of the Member States are informed that another Member

State has authorised a medicinal product that is the subject of a marketing authorisation

application in the Member State concerned, they shall reject the application unless it was

submitted in compliance with the provisions referred to in Articles 35 and 36.

Marketing authorisations granted under the decentralised procedure for national marketing

authorisation shall be valid only in those Member States of the competent authoritiesy that

granted it the authorisations

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Article 34

Decentralised procedure for national marketing authorisations

With a view to obtain a national marketing authorisation for a medicinal product in several

Member States in respect of the same medicinal product under the decentralised procedure for

national marketing authorisation, an applicant shall submit a marketing authorisation

application based on an identical dossier to the competent authority of the Member State

chosen by the applicant, to prepare an assessment report on the medicinal product in

accordance with Article 43(5) and to act in accordance with this Section (‘reference Member

State for the decentralised procedure’), and to the competent authorities in the other Member

States concerned.

The application for marketing authorisation shall contain:

(a) the particulars and documentations referred to in Articles 6, 9 to 14 and 62;

(b) a list of Member States concerned by the application.

The applicant shall inform all the competent authorities of all Member States of its application

at the time of submission. If necessary to meet the needs of patients in that Member State,

Tthe competent authority of a Member State may request for justified public health reasons to

enter the procedure and shall inform the applicant and the competent authority of the

reference Member State for the decentralised procedure of its request within 30 days from the

date of submission of the application. The applicant shall provide the competent authorities of

those Member States entering the procedure with the application without undue delay. The

Member State that requests to enter the decentralised procedure under this paragraph

shall be considered as Member State concerned.

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3a. Where, in the course of the validation referred to in Article 29, paragraph 1, point (a),

the competent authority of the reference Member State for the decentralised procedure

considers that the information in the submitted marketing authorisation application is

incomplete or contains deficiencies to the extent that this may prevent the evaluation of

the application, it shall inform the applicant accordingly and shall set a time limit for

submitting the missing information and documentation. If the applicant fails to provide

the missing information and documentation within the time limit set, the application

shall be considered to have been withdrawn by the applicant in the reference Member

State of the decentralised procedure and in all Member States concerned.

In cases where on examination of an application for a marketing authorisation the competent

authority of the reference Member State for the decentralised procedure considers that the

submitted data are not of sufficient quality or maturity for the completion of the examination

of the application, the examination can be terminated within 90 days of the date of the

validation of the application.

Prior to the termination, Tthe competent authority of the reference Member State for the

decentralised procedure shall summarise the deficiencies in writing. On this basis, the

competent authority of the reference Member State for the decentralised procedure shall

inform the applicant and the competent authorities of the Member States concerned

accordingly and set a time limit to address the deficiencies. The application shall be

suspended until the applicant addresses the deficiencies. If the applicant fails to address those

deficiencies within the time limit set by the competent authority of the reference Member

State for the decentralised procedure, the assessment shall be terminated and the

application shall be considered as withdrawn by the applicant in all Member States in

which it was submitted.

The competent authority of the reference Member State for the decentralised procedure shall

inform the competent authorities of the Member States concerned and the applicant

accordingly.

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Within 120 days after the date of the validation of the application, the competent authority of

the reference Member State for the decentralised procedure shall prepare an assessment report,

a summary of product characteristics, the labelling and the package leaflet and shall send them

to the Member States concerned and to the applicant.

Within 60 90 days of receipt of the assessment report, the competent authorities of the

Member States concerned shall approve the assessment report, the summary of product

characteristics and the labelling and package leaflet and shall inform the competent authority

of the reference Member State for the decentralised procedure accordingly. The competent

authority of the reference Member State for the decentralised procedure shall record the

agreement of all parties, close the procedure and inform the applicant accordingly.

6a. Within 7 days of the receipt of the information under paragraph 6 the applicant shall

submit the high quality translations of the summary of product characteristics, the

labelling and the package leaflet to the each of the competent authorities concerned.

Within 30 days after acknowledgement of the agreement receipt of the translations referred

to in paragraph 6a, the competent authorities of all Member States concerned in which an

application has been submitted in accordance with paragraph 1 shall adopt a decision

according to Articles 43 to 45 and in conformity with the approved assessment report, the

summary of product characteristics and the labelling and package leaflet as approved.

Section 4

Mutual recognition of national marketing authorisations

Article 35

Scope of mutual recognition procedure for national marketing authorisations

Where the medicinal product has already received a marketing authorisation in

accordance with Articles 43 to 45 at the time of application, it shall be recognised in

other Member States in accordance with the procedure laid down in Article 36.

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An application for marketing authorisation for mutual recognition procedure for national

marketing authorisation, granted under Articles 43 to 45 and in accordance with Article 32,

shall be submitted to the competent authorities of other Member States in accordance with the

procedure laid down in Article 36.

Article 36

Mutual recognition procedure for national marketing authorisations

An application for mutual recognition of a marketing authorisation, granted under Articles 43

to 45 and in accordance with Article 32, in several Member States in respect of the same

medicinal product shall be submitted to the competent authority of one of the Member States

that granted the a marketing authorisation (‘reference Member State for the mutual

recognition procedure’) and to the competent authorities of the Member States concerned

where the applicant seeks to obtain a national marketing authorisation.

Application shall include a list of Member States concerned by the application.

The competent authority of the reference Member State for the mutual recognition procedure

shall reject refuse the request an application for mutual recognition of marketing

authorisation of medicinal product within a year from the granting of that marketing

authorisation, unless the competent authority of the Member State informs the competent

authority of the reference Member State for the mutual recognition procedure of its interest in

this medicinal product.

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The applicant shall inform the competent authorities of all Member States of its application at

the time of submission referred to in paragraph 1. If necessary to meet the needs of

patients in that Member State, Tthe competent authority of a Member State may request for

justified public health reasons to enter the procedure and shall inform the applicant and the

competent authority of the reference Member State for the mutual recognition procedure of its

request within 30 days from the date of submission of the application. The applicant shall

provide the competent authorities of those Member States entering the procedure with the

application without undue delay. The Member State that requests to enter the mutual

recognition procedure under this paragraph shall be considered as Member State

concerned.

If tThe competent authorityies of the Member States concerned so require, the marketing

authorisation holder shall request the competent authority of the reference Member State for

the mutual recognition procedure shall send the assessment report together with the

approved summary of product characteristics, labelling and package leaflet to the

concerned Member States and to the applicant within 90 30 days after the date of

validation of the application. to update the assessment report drawn on the medicinal

concerned by the application. In that case, the reference Member State shall update the

assessment report within 90 days after validation of the application. If the competent

authorities of the Member States concerned do not require the update of the assessment report,

the reference Member State shall provide the assessment report within 30 days In case the

update of the assessment report is requested by the Member States concerned, the

procedure may be extended to 90 days.

Within 60 days of receipt of the assessment report, the competent authorities of the Member

States concerned shall approve the assessment report, the summary of product characteristics,

the labelling and package leaflet and shall inform the competent authority of the reference

Member State accordingly.

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The competent authority of reference Member State for the mutual recognition procedure

shall record the agreement of all parties, close the procedure and inform the applicant

accordingly. The assessment report together with the summary of product characteristics,

labelling and package leaflet approved by the competent authority of the reference Member

State for the mutual recognition procedure shall be sent to the Member States concerned and

to the applicant.

7a. Within 7 days of the receipt of the information under paragraph 7 the applicant shall

submit the high quality translations of the the summary of product characteristics, the

labelling and the package leaflet to the each of the competent authorities concerned.

Within 30 days after acknowledgement of the agreement the receipt of the translations

referred to in paragraph 7a, the competent authorities of all Member States concerned in

which an application has been submitted in accordance with paragraph 1 shall adopt a

decision according to Articles 43 to 45 in conformity with the approved assessment report, the

summary of product characteristics, the labelling and package leaflet as approved.

Section 5

Coordination of national marketing authorisation

Article 37

Coordination group for decentralised and mutual recognition procedures

A coordination group for decentralised and mutual recognition procedures (‘coordination

group’) shall be set up for the following purposes:

(a) the examination of any question relating to a national marketing authorisation of a

medicinal product in two or more Member States in accordance with the procedures laid

down in Sections 3, 4 and 5 of this Chapter, and Article 95;

(b) the examination of questions related to the pharmacovigilance of medicinal products

covered by national marketing authorisations, in accordance with Articles 108, 110,

112, 116 and 121;

in accordance with Article 93(1)

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(d) the establishment and publication of a list of medicinal products for which a

harmonised summary of product characteristics is to be drawn up, in accordance

with Article 40;

(e) to reach agreement on the harmonisation of summary of product characteristics,

in accordance with Article 40.

For the fulfilment of its pharmacovigilance tasks contemplated under first subparagraph, point

(b), including approving risk management systems and monitoring their effectiveness, the

coordination group shall rely on the scientific assessment and the recommendations of the

Pharmacovigilance Risk Assessment Committee referred to in Article 149 of [revised

Regulation (EC) No 726/2004].

The coordination group shall be composed of one representative per Member State appointed

for a renewable period of three years. Member States may appoint an alternate for a

renewable period of three years. Members of the coordination group may arrange to be

accompanied by experts.

Members of the coordination group and experts shall, for the fulfilment of their tasks, rely on

the scientific and regulatory resources available to competent authorities of the Member

States. Each competent authority of the Member State shall monitor the level of expertise of

the evaluations carried out and facilitate the activities of nominated coordination group

members and experts.

Article 147 of [revised Regulation (EC) No 726/2004] shall apply to the coordination group as

regards transparency and the independence of its members.

The Agency shall provide the secretariat of this coordination group. The coordination group

shall draw up its own Rules of Procedure, which shall enter into force after a favourable

opinion has been given by the Commission. These Rules of Procedure shall be made publicly

available.

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The Executive Director of the Agency or the representative of the Executive Director and

representatives of the Commission shall be entitled to attend all meetings of the coordination

group.

The members of the coordination group shall ensure that there is appropriate coordination

between the tasks of that group and the work of competent authorities of the Member States,

including the consultative bodies concerned with the marketing authorisation.

Where otherwise provided for in this Directive, within the coordination group, all Member

States representatives shall use their best endeavours to reach a position by consensus on the

action to be taken. If such a consensus cannot be reached, the position of the majority of the

Member States represented within the coordination group shall prevail.

Members of the coordination group shall be required, even after their duties have ceased, not

to disclose information of the kind covered by the obligation of professional secrecy.

Article 38

Divergent positions of Member States in decentralised or mutual recognition procedure

If, at the end of the period laid down in Articles 34(6) or 36(6), there is disagreement between

Member States on whether the marketing authorisation can be issued, on the grounds of

potential serious risk to public health, the disagreeing Member States concerned shall give a

detailed explanation of the points of disagreement and the reasons for its position to the

reference Member State, to the other Member States concerned and to the applicant. The

points of disagreement shall be referred to the coordination group without undue delay.

Guidelines to be adopted by the Commission shall define a potential serious risk to public

health.

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Within the coordination group, all disagreeing Member States concerned shall use their best

endeavours to reach agreement on the action to be taken. They shall allow the applicant the

opportunity to make its point of view known orally or in writing. If, within 60 days of the

communication of the points of disagreement, the Member States reach an agreement by

consensus, the reference Member State shall record the agreement, close the procedure and

inform the applicant accordingly. The procedure laid down in Articles 34(7) or 36(8) shall

apply.

If within the 60-day period laid down in paragraph 3, an agreement by consensus cannot be

reached, the position of the majority of the Member States represented within the coordination

group, with a detailed description of the matters on which the other Member States have

been unable to reach an agreement and of all the divergent positions of Member States

presented, shall be forwarded to the Commission,. The coordination group may

recommend the Commission to refer the matter to the Committee for Medicinal

Products for Human Use.

which The Commission shall apply the procedure laid down in Articles 41 and 42. Where

the Commission on its own initiative or based on the recommendation of the

coordination group considers that the matter shall be referred to the Committee for

Medicinal Products for Human Use, Article 41 shall also apply.

In the circumstances referred to in paragraph 4, Member States that have approved the

assessment report, the summary of product characteristics, the labelling and package leaflet of

the reference Member State may, at the request of the applicant, authorise the medicinal

product without waiting for the outcome of the procedure laid down in Article 412. In that

event, the national marketing authorisation granted shall be without prejudice to the outcome

of that procedure.

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Article 39

Referral procedure of divergent decisions of Member States

If applications for a national marketing authorisation have been submitted in accordance with

Articles 6 and 9 to 14 for a particular medicinal product, and if Member States have adopted

divergent decisions concerning the national marketing authorisation, its variation, suspension or

revocation or the summary of product characteristics, the competent authority of the Member State,

the Commission or the marketing authorisation holder may refer the matter to the Committee for

Medicinal Products for Human Use for the application of the procedure laid down in Articles 41

and 42.

Article 40

Harmonisation of summary of product characteristics

In order to promote the harmonisation of national marketing authorisations for medicinal

products throughout the Union, the competent authorities of the Member States shallmay,

each year, forward to the coordination group referred to in Article 37 a list of medicinal

products for which a harmonised summary of product characteristics is to be drawn up.

The coordination group shall may lay down a list of medicinal products for which a

harmonised summary of product characteristics is to be drawn up, taking into account the

proposals from the competent authorities of all Member States, and shall decide on the

harmonisation of summary of product characteristics for those medicinal products and

shall forward that list toinform the Commission.

The Commission or the competent authority of a Member State, in agreement with the

Agency and taking into account the views of interested parties, may refer the matter

concerning the harmonisation of summary of products characteristics of those medicinal

products to the Committee for Medicinal Products for Human Use for the application of the

procedure laid down in Articles 41 and 42.

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3a. If, within the coordination group, the Member States represented reach agreement on

the action to be taken by consensus, the chairman shall record the agreement and send it

to the marketing authorisation holder and the Member States. The Member States shall

adopt necessary measures to vary the marketing authorisations concerned in accordance

with the timetable for implementation determined in the agreement. The marketing

authorisation holder shall submit to the competent authorities of the Member States an

appropriate application for a variation of marketing authorisation, including an

updated summary of product characteristics and package leaflet within the determined

timetable for implementation.

If an agreement by consensus cannot be reached, the position of the majority of the

Member States represented within the coordination group, with a detailed description of

the matters on which the other Member States have been unable to reach an agreement

and of all the divergent positions of Member States presented, shall be forwarded to the

Commission. The Commission shall apply the procedure laid down in Article 42.

Article 41

Scientific evaluation by the Committee for Medicinal Products for Human Use in a referral

procedure

When reference is made to the procedure laid down in this Article, the Committee for

Medicinal Products for Human Use referred to in Article 148 of [revised Regulation (EC) No

726/2004] shall consider the matter concerned and shall issue a reasoned opinion within 60

days from the date when the matter was referred to it.

However, in cases submitted to the Committee for Medicinal Products for Human Use in

accordance with Articles 39, 40 and 95, this period may be extended by the Committee for

Medicinal Products for Human Use for a further period of up to 90 days.

On a proposal from its chairperson, the Committee for Medicinal Products for Human Use may

agree to a shorter deadline.

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In order to consider the matter, the Committee for Medicinal Products for Human Use shall

appoint one of its members to act as rapporteur. The Committee may also appoint individual

experts to advise it on specific questions. When appointing experts, the Committee for

Medicinal Products for Human Use shall define their tasks and specify the time limit for the

completion of these tasks.

Before issuing its opinion, the Committee for Medicinal Products for Human Use shall

provide the applicant or the marketing authorisation holder with an opportunity to present

written or oral explanations within a time limit which it shall specify.

The opinion of the Committee for Medicinal Products for Human Use shall be accompanied

by a summary of product characteristics, the labelling and package leaflet.

If necessary, the Committee for Medicinal Products for Human Use may call upon any other

person to provide information relating to the matter before it or consider a public hearing.

The Agency shall, in consultation with the parties concerned, draw up Rules of Procedure on

the organisation and conduct of public hearings, in accordance with Article 163 of [revised

Regulation (EC) No 726/2004].

The Committee for Medicinal Products for Human Use may suspend the time limits referred

to in paragraph 1 in order to allow the applicant or the marketing authorisation holder to

prepare explanations.

The Agency shall without undue delay inform the applicant or the marketing authorisation

holder where the opinion of the Committee for Medicinal Products for Human Use provides

that:

(a) the application does not satisfy the criteria for a marketing authorisation;

(b) the summary of product characteristics proposed by the applicant or the marketing

authorisation holder in accordance with Article 62 is to be amended;

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considered essential for the safe and effective use of the medicinal product, including

pharmacovigilance;

(d) a marketing authorisation is to be suspended, varied or revoked;

(e) the medicinal product satisfies the conditions set out in Article 83 regarding medicinal

products addressing an unmet medical need.

Within 12 days after receipt of the opinion, the applicant or the marketing authorisation holder

may notify the Agency in writing of its intention to request a re-examination of the opinion. In

that case, they shall forward to the Agency the detailed grounds for the request within 60 days

after receipt of the opinion.

Within 60 days following receipt of the grounds for the request, the Committee for Medicinal

Products for Human Use shall re-examine its opinion in accordance with Article 12(2), third

subparagraph, of [revised Regulation (EC) No 726/2004]. The reasons for the conclusion

reached further to its re-examination shall be annexed to the assessment report referred to in

Article 12(2), third subparagraph, of [revised Regulation (EC) No 726/2004].

Within 12 days after its adoption, the Agency shall forward the final opinion of the

Committee for Medicinal Products for Human Use to the competent authorities of the

Member States, to the Commission and to the applicant or the marketing authorisation holder,

together with a report describing the assessment of the medicinal product and stating the

reasons for its conclusions.

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In the event of an opinion in favour of granting or maintaining a marketing authorisation to

place the medicinal product concerned on the market, the following documents shall be

annexed to the final opinion:

(a) a summary of product characteristics, as referred to in Article 62;

(b) the details of any conditions affecting the marketing authorisation within the meaning of

paragraph 4, first subparagraph, point (c);

effective use of the medicinal product;

(d) the labelling and package leaflet.

Article 42

Commission decision

Within 12 days of receipt of the opinion of the Committee for Medicinal Products for Human

Use, or the position of the majority of the Member States represented within the

coordination group, as set out in Article 38 (4), the Commission shall submit to the

Standing Committee on Medicinal Products for Human Use referred to in Article 214(1) a

draft of the decision on the application, on the basis of the requirements set out in this

Directive.

In duly justified cases, the Commission may return the opinion to the Agency or the

coordination group, as applicable, for further consideration.

Where a draft decision envisages the granting of a marketing authorisation, it shall include or

make reference to the documents referred to in Article 38(5) or 41(5), second subparagraph.

Where a draft decision differs from the opinion of the Agency or of the coordination group,

the Commission shall provide a detailed explanation of the reasons for the differences.

The Commission shall send the draft decision to the competent authorities of the Member States

and the applicant or the marketing authorisation holder.

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The Commission shall, by means of implementing acts, adopt a final decision within 12 days

after obtaining the opinion of the Standing Committee on Medicinal Products for Human Use.

Those implementing acts shall be adopted in accordance with the examination procedure

referred to in Article 214(2) and (3).

Where a Member State raises important new questions of a scientific or technical nature that

have not been addressed in the opinion delivered by the Agency or by the coordination group,

the Commission may refer the application back to the Agency or to the coordination group,

as applicable, for further consideration. In that case, the procedures set out in paragraphs 1 and

2 shall start again upon reception of the reply of the Agency or of the coordination group.

The decision referred to in paragraph 2 shall be addressed to all Member States and forwarded

for information to the applicant or the marketing authorisation holder. The Member States

concerned and the reference Member State shall adopt a decision to either grant, suspend,

refuse or revoke the marketing authorisation, or vary its terms as necessary to comply with

the decision referred to in paragraph 2 within 30 days following its notification. In the

decision to grant, suspend, refuse, revoke or vary the marketing authorisation, the Member

States shall refer to the decision adopted pursuant to paragraph 2. They shall inform the

Agency or the coordination group accordingly, as applicable. The coordination group

may recommend the Commission to refer the matter to the Committee for Medicinal

Products for Human Use. Where the Commission on its own initiative or based on the

recommendation of the coordination group considers that the matter shall be referred to

the Committee for Medicinal Products for Human Use, Article 41 shall also apply.

Where the scope of the procedure initiated under Article 95 includes medicinal products

covered by centralised marketing authorisation pursuant to Article 95(2), third subparagraph,

the Commission shall, where necessary, adopt decisions to vary, suspend or revoke the

marketing authorisations or to refuse the renewal of the marketing authorisations concerned in

accordance with this Article.

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Section 6

Results of examination of a national marketing authorisation application

Article 43

Granting of the national marketing authorisation

When a competent authority of the Member State grants a national marketing authorisation, it

shall inform the applicant of the marketing authorisation of the summary of product

characteristics, the package leaflet, the labelling as well as any conditions established in

accordance with Articles 44 and 45 together with any deadlines for the fulfilment of those

conditions.

The competent authorities of the Member States shall take all necessary measures to ensure

that the information given in the summary of product characteristics is in conformity with that

accepted when the national marketing authorisation is granted or subsequently.

The competent authorities of the Member States shall, without undue delay, make publicly

available the national marketing authorisation together with the summary of product

characteristics, the package leaflet as well as any conditions established in accordance with

Articles 44, 45 and any obligations imposed subsequently in accordance with Article 87,

together with any deadlines for the fulfilment of those conditions and obligations for each

medicinal product that they have authorised.

The competent authority of the Member State may consider and decide upon additional

evidence available, independently from the data submitted by the marketing authorisation

holder. On that basis, the summary of product characteristics shall be updated if the additional

evidence has an impact on the benefit-risk balance of a medicinal product.

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The competent authorities of the Member States shall draw up an assessment report and make

comments on the file as regards the results of the pharmaceutical and non-clinical tests, the

clinical studies, the risk management system, the environmental risk assessment and the

pharmacovigilance system of the medicinal product concerned.

The competent authorities of the Member States shall make the assessment report publicly

available without undue delay, together with the reasons for their opinion, after deletion of

any information of a commercially confidential nature. The justification shall be provided

separately for each therapeutic indication applied for.

The public assessment report referred to in paragraph 5 shall include a summary written in a

manner that is understandable to the public. The summary shall contain, in particular, a

section relating to the conditions of use of the medicinal product.

The competent authorities of the Member States shall, without undue delay, make

publicly available the national marketing authorisation together with the summary of

product characteristics, the package leaflet as well as any conditions established in

accordance with Articles 44, 45 and any obligations imposed subsequently in accordance

with Article 87, together with any deadlines for the fulfilment of those conditions and

obligations for each medicinal product that they have authorised.

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Article 44

National marketing authorisation subject to conditions

A marketing authorisation for a medicinal product may be granted subject to one or more of

the following conditions:

(a) to take certain measures for ensuring the safe use of the medicinal product to be

included in the risk management system;

(b) to conduct post-authorisation safety studies;

that are stricter than those referred to in Chapter IX;

(d) any other conditions or restrictions with regard to the safe and effective use of the

medicinal product;

(e) the existence of an adequate pharmacovigilance system;

(f)

to conduct post-authorisation efficacy studies where concerns relating to some aspects

of the efficacy of the medicinal product are identified and can be resolved only after the

medicinal product has been marketed;

(g) in case of medicinal products for which there is substantial uncertainty as to the surrogate

endpoint relation to the expected health outcome, where appropriate and relevant for the

benefit-risk balance, a post-authorisation obligation to substantiate the clinical benefit;

(ga) in case of the environmental risk assessment suffering from deficiencies at the time

of application, or if the risk identified in the environmental risk assessment has not

been sufficiently addressed by the applicant, to address the deficiencies within an

agreed timeframe and if required to implement appropriate risk mitigation

measures;

(h) to conduct post-authorisation environmental risk assessment studies, collection of

monitoring data or information on use, where identified or potential concerns about risks

to the environment or public health, including antimicrobial resistance need to be further

investigated after the medicinal product has been marketed;

(i)

to conduct post-authorisation studies to improve the safe and effective use of the

medicinal product;

(j)

where appropriate, to carry out medicinal product-specific validation studies to replace

animal-based control methods with non-animal-based control methods.

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An obligation to conduct post authorisation efficacy studies referred to in the first subparagraph,

point (f), shall be based on the delegated acts adopted pursuant to Article 88.

The marketing authorisation shall lay down deadlines for the fulfilment of the conditions

referred to in paragraph 1, first subparagraph, where necessary.

Article 45

National marketing authorisation under exceptional circumstances

In exceptional circumstances where, in an application under Article 6 for a marketing

authorisation of a medical product, or in an application under Article 92 for a new therapeutic

indication of an existing marketing authorisation, an applicant is unable to provide

comprehensive data on the efficacy and safety of the medicinal product under normal

conditions of use, the competent authority of the Member State may, by derogation to Article

6, grant an authorisation under Article 43, subject to specific conditions, where the following

requirements are met:

(a) the applicant has demonstrated, in the application file, that there are objective and

verifiable reasons not to be able to submit comprehensive data on the efficacy and

safety of the medicinal product under normal conditions of use based on one of the

grounds set out in Annex II;

(b) except for the data referred to in point (a), the application file is complete and satisfies

all the requirements of this Directive;

Member States, in particular to ensure the safety of the medicinal product as well to

ensure that the marketing authorisation holder notifies to the competent authorities of

the Member States any incident relating to its use and takes appropriate action where

necessary.

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The maintenance of the authorised new therapeutic indication and the validity of the national

marketing authorisation shall be linked to the reassessment of the conditions set out in

paragraph 1 after two years or within a shorter deadline specified by the competent

authority from the date when the new therapeutic indication was authorised or the marketing

authorisation was granted, and thereafter at a risk-based frequency to be determined by the

competent authorities of the Member State and specified in the marketing authorisation.

This reassessment shall be conducted on the basis of an application by the marketing

authorisation holder to maintain the authorised new therapeutic indication or renew the

marketing authorisation under exceptional circumstances.

Article 46

Validity and renewal of marketing authorisation

Without prejudice to paragraph 4, a marketing authorisation for a medicinal product shall be

valid for an unlimited period.

By way of derogation from the first subparagraph, a national marketing authorisation granted

in accordance with Article 45(1) shall be valid for five years and be subject to renewal in

accordance with paragraph 2.

By way of derogation from the first subparagraph, a competent authority of the Member State

may decide at the time of granting the national marketing authorisation, on objectively and

duly justified grounds relating to safety of the medicinal product, to limit the validity of the

national marketing authorisation to five years.

The marketing authorisation holder may submit an application for a renewal of a national

marketing authorisation granted under paragraph 1, second or third subparagraph. Such

application shall be submitted at least nine months before the national marketing authorisation

ceases to be valid.

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Once the application for a renewal has been submitted within the time limit provided for in

paragraph 2, the national marketing authorisation shall remain valid until the competent

authority of the Member State adopts a decision.

The competent authority of the Member State may renew the national marketing authorisation

on the basis of a re-evaluation of the benefit-risk balance. Once renewed, the marketing

authorisation shall be valid for an unlimited period.

Article 47

Refusal of a national marketing authorisation

The national marketing authorisation shall be refused if, after verification of the particulars

and documentations referred to in Article 6 and subject to the specific requirements laid down

in Articles 9 to 14, the view is taken that:

(a) the benefit-risk balance is not considered to be favourable;

(b) that the applicant has not properly or sufficiently demonstrated the quality, safety or

efficacy of the medicinal product;

(d) the environmental risk assessment is incomplete or insufficiently substantiated by the

applicant or if the risks identified in the environmental risk assessment have not been

sufficiently addressed by the applicant, unless these deficiencies are justified by the

applicant and either post-authorisation environmental risk assessment studies can

be requested as referred to in Article 44 (1) (h), or the identified risks can be

mitigated with appropriate risk mitigation measures as referred to in Article 44 (1)

(ga) or both;

(e) the labelling and package leaflet proposed by the applicant are not in accordance do not

comply with with Chapter VI or they are not in accordance with the particulars

listed in the summary of product characteristics.

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The national marketing authorisation shall also be refused if any particulars or

documentations submitted in support of the application do not comply with Article 6,

paragraphs 1 to 6, and Articles 9 to 14.

The applicant or the marketing authorisation holder shall be responsible for the accuracy of

the particulars and documentations submitted..

Section 7

Specific requirements for paediatric medicinal products

Article 48

Compliance with the paediatric investigation plan

The competent authority of the Member State for which an application for marketing

authorisation or variation of a marketing authorisation is submitted under the provisions of

this Chapter or of the Chapter VIII, shall verify whether it complies with the requirements laid

down in Article 6(5).

Where the application is submitted in accordance with the procedure set out in this Chapter,

Sections 3 and 4, the verification of compliance, including, as appropriate, requesting an

opinion of the Agency in accordance with paragraph 3, point (b), shall be conducted by the

reference Member State.

The Committee for Medicinal Products for Human Use, as referred to in Article 148 of

[revised Regulation (EC) No 726/2004] may, in the following cases, be requested to give its

opinion as to whether studies conducted by the applicant are in compliance with the agreed

paediatric investigation plan as defined in Article 74 of [revised Regulation (EC) No

726/2004]:

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(a) by the applicant, prior to submitting an application for a marketing authorisation or for a

variation of a marketing authorisation;

(b) by the competent authority of the Member State, when validating an application for a

marketing authorisation or for a variation of a marketing authorisation that does not

already include such an opinion.

In the case of a request in accordance with paragraph 3, point (a), the applicant shall not

submit its application until the Committee for Medicinal Products for Human Use has

provided its opinion, and a copy thereof shall be annexed to the application.

Member States shall take due account of an opinion drawn up in accordance with paragraph 3.

When the competent authority of the Member State, during the scientific assessment of a valid

application for a marketing authorisation or a variation of a marketing authorisation,

concludes that the studies are not in conformity with the agreed paediatric investigation plan,

the medicinal product shall not be eligible for the rewards and incentives provided for in

Article 86.

Article 49

Data deriving from a paediatric investigation plan

Where a marketing authorisation or a variation of a marketing authorisation, is granted in

accordance with the provisions under this Chapter or of the provisions under Chapter VIII:

(a) the results of all clinical studies, conducted in compliance with an agreed paediatric

investigation plan as referred to in Article 6(5), point (a), shall be included in the

summary of product characteristics and, if appropriate, in the package leaflet, or

(b) any agreed waiver as referred to in Article 6(5), points (b) and (c), shall be recorded in

the summary of product characteristics and, if appropriate, in the package leaflet of the

medicinal product concerned.

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If the application complies with all the measures contained in the agreed completed paediatric

investigation plan and if the summary of product characteristics reflects the results of studies

conducted in compliance with that agreed paediatric investigation plan, the competent

authority of the Member State shall include within the marketing authorisation a statement

indicating compliance of the application with the agreed completed paediatric investigation

plan.

An application for new therapeutic indications, including paediatric indications, new

pharmaceutical forms, new strengths and new routes of administration of medicinal products

authorised in accordance with the provisions under this Chapter or of the provisions under

Chapter VIII and which are protected either by a supplementary protection certificate under

[Regulation (EC) No 469/2009 - OP please replace reference by new instrument when

adopted], or by a patent which qualifies for the granting of the supplementary protection

certificate, may be submitted under the procedure laid down in Articles 541 and 642.

The procedure referred to in paragraph 3 shall be limited to the assessment of the specific

section of the summary of product characteristics to be varied.

Chapter IV

Prescription status

Article 50

Prescription status of medicinal products

When a marketing authorisation is granted, the competent authorities shall, by applying the

criteria laid down in Article 51, specify the prescription status of the medicinal product as:

(a) a medicinal product subject to medical prescription; or

(b) a medicinal product not subject to medical prescription.

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The competent authorities may fix sub-categories for medicinal products that are subject to

medical prescription. In that case, they shall specify the following prescription status:

(a) medicinal products subject to medical prescription for renewable or non-renewable

delivery;

(b) medicinal products subject to special medical prescription;

specialised areas.

Article 51

Medicinal products subject to medical prescription

A medicinal product shall be subject to medical prescription where it:

(a) is likely to present a danger either directly or indirectly, even when used correctly, if

used without medical supervision;

(b) is frequently and to a very wide extent used incorrectly, and as a result is likely to

present a direct or indirect danger to human health;

require further investigation;

(d) is normally prescribed by a doctor to be administered parenterally;

(e) is an antimicrobial, unless intended for topical or ;

(f)

contains an active substance which are is

(i)

persistent, bioaccumulative and toxic, or

(ii) very persistent and very bioaccumulative, or

(iii) persistent, mobile and toxic, or

(iv) very persistent and very mobile, and for which medical prescription is required as

risk minimisation measure with regard to the environment is required, unless

other circumstances of use justify the use of the medicinal product and the

patient safety require otherwise.

and for which medical prescription is required as risk minimisation measure with regard

to the environment is required, unless other circumstances of use justify the use

of the medicinal product and the patient safety require otherwise.

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Member States may set additional conditions on the prescription of antimicrobials or active

substances referred to in paragraph 1, point f, restrict the validity of medical prescription

and limit the quantities prescribed to the amount required for the treatment or therapy

concerned or submitting certain antimicrobial medicinal products to special medical

prescription or restricted prescription.

Member States may decide to make antimicrobials intended for topical use subject to

medical prescription.

Where Member States provide for the sub-category of medicinal products subject to special

medical prescription, they shall take account of the following factors:

(a) the medicinal product contains, in a non-exempt quantity, a substance classified as a

narcotic or a psychotropic substance within the meaning of the international

conventions;

(b) the medicinal product is likely, if incorrectly used, to present a substantial risk of

medicinal abuse, to lead to addiction or be misused for illegal purposes; or

could be considered as belonging to the group set out in point (ba) as a precautionary

measure.

Where Member States provide for the sub-category of medicinal products subject to restricted

prescription, they shall take account of the following factors:

(a) the medicinal product, because of its pharmaceutical characteristics or novelty or in the

interests of public health, is reserved for treatments that can only be followed in a

hospital environment;

(b) the medicinal product is used in the treatment of conditions that must be diagnosed in a

hospital environment or in institutions with adequate diagnostic facilities, although

administration and follow-up may be carried out elsewhere;

adverse reactions requiring a prescription drawn up as required by a specialist and

special supervision throughout the treatment.

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A competent authority may waive application of criteria set out in the paragraphs 1 (a), (b),

(c), (d) and (f) , 3 and 4 regarding the medical prescription, having regard to:

(a) the maximum single dose, the maximum daily dose, the strength, the pharmaceutical

form, certain types of packaging; or

(b) other circumstances of use that it has specified.

If a competent authority does not designate medicinal products into sub-categories referred to

in Article 50(2), it shall nevertheless take into account the criteria laid down in paragraphs 3

and 4 in determining whether any medicinal product shall be classified as a medicinal product

subject to medical prescription.

Article 52

Medicinal products not subject to medical prescription

A Mmedicinal products shall not be subject to medical prescription if the medicinal product does

shall be those that do not meet the criteria laid down in Article 51, paragraphs 1, 3 and 4 or if

Article 51, paragraph 5, is applicable.

Article 53

List of medicinal products subject to medical prescription

The competent authorities shall draw up a list of the medicinal products subject, on their territory, to

medical prescription, specifying, if necessary, the category of prescription status. They shall update

this list annually.

Article 54

Amendment of prescription status

When new facts are brought to their attention, the competent authorities shall examine and, as

appropriate, amend the prescription status of a medicinal product by applying the criteria listed in

Article 51. In such cases, the marketing authorisation holder shall on their own initiative or on

request of a competent authority, submit a variation to amend the prescription status.

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In case of a potential or actual shortage of a medicinal product that puts patients' needs or

public health at risk, a competent authority may temporarily amend the prescription status of

a medicinal product. The amendment shall be withdrawn as soon as the shortage or risk of

shortage ceases.

Article 55

Data protection of evidence for the change of prescription status

Where a change of prescription status of a medicinal product has been authorised on the basis of

significant non-clinical tests or clinical studies, the competent authority shall not refer to the results

of those tests or studies when examining an application by another applicant for or marketing

authorisation holder for a change of prescription status of the same substance for one year after the

initial change was authorised.

Chapter V

Obligations and liability of the marketing authorisation holder

Article 56

General obligations

The marketing authorisation holder shall be responsible for the making available on the

market of the medicinal product covered by the marketing authorisation it has been granted.

The designation of a marketing authorisation holder representative shall not relieve the

marketing authorisation holder of its legal responsibility.

The marketing authorisation holder of a medicinal product placed on the market in a Member

State shall notify the competent authority of the Member State concerned of the date of actual

placing on the market of the medicinal product in that Member State, taking into account the

various presentations authorised.

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2a. Where a marketing authorisation is withdrawn, for the medicinal products that were

previously placed on the market under that marketing authorisation all relevant

obligations and post-marketing provisions of this Directive and of [revised Regulation

726/2004/EC] shall continue to apply as appropriate for the period agreed with the

competent authority.

The marketing authorisation holder of a medicinal product placed on the market in a Member

State shall, within the limits of its responsibility, ensure appropriate stock levels and

continued supplies of that medicinal product to wholesale distributors, pharmacies or persons

authorised to supply medicinal products so that the needs of patients in the Member State in

question are covered.

The arrangements for implementing the first subparagraph should, moreover, be justified on

grounds of public health protection and be proportionate in relation to the objective of such

protection, in compliance with the Treaty rules, particularly those concerning the free

movement of goods and competition.

The marketing authorisation holder shall, at all stages of manufacturing and distribution

ensure that the starting materials and ingredients of the medicinal products and the medicinal

products themselves comply with the requirements of this Directive and, where relevant, the

[revised Regulation (EC) No 726/2004] and other Union law and shall verify that such

requirements are met.

For integral combination of a medicinal product with a medical device and for combinations

of a medicinal product with a product other than a medical device, the marketing authorisation

holder shall be responsible for the whole product in terms of compliance of the medicinal

product with the requirements of this Directive and the [revised Regulation (EC) No

726/2004].

The marketing authorisation holder shall be established in the Union.

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Where the marketing authorisation holder considers or has reason to believe that the

medicinal product it has made available on the market is not in conformity with the marketing

authorisation or this Directive and the [revised Regulation (EC) No 726/2004] it shall

immediately take the necessary corrective actions to bring that medicinal product into

conformity, to withdraw it or recall it, as appropriate. The marketing authorisation holder

shall immediately inform the competent authorities and the distributors concerned to that

effect.

Upon request, the marketing authorisation holder shall provide the competent authorities with

free samples in sufficient quantities to enable controls to be made on the medicinal products

that it has placed on the market.

Upon request the marketing authorisation holder shall provide the competent authority with

all data relating to the volume of sales of the medicinal product, and any data in its possession

relating to the volume of prescriptions.

Article 56a

Specific requirements on making available and supplying of a medicinal product in a Member

State

With a view to facilitating access to a medicinal product covered by a valid marketing

authorisation within the territory of a Member State subject to regulatory protection

pursuant to Article 80, or, if applicable, the market exclusivity in accordance with

Article 72 of [revised Regulation 726/2004], a Member State may request the marketing

authorisation holder of that medicinal product to make place it on the market available

of that Member State and supply it, on the market of that Member State in sufficient

quantities and in the presentations necessary to cover the needs of patients in that

Member State, as specified by that Member State.

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For the purposes of paragraph 1, a Member State may require the marketing

authorisation holder to carry out specific actions pursuant to national law, including but

not limited to, the following:

submit a valid pricing and reimbursement application;

fulfilling specific requirements for marketing authorisation holders in

procurement procedures;

establishing a roll-out plan.

The arrangements to implement the requirements referred to in this paragraph shall be

proportionate to the objective pursued and in compliance with Union law.

The roll-out plan referred to in paragraph 2, point (c), shall include information about

the supply of the medicinal product by the marketing authorisation holder over a given

period in the Member State concerned. The roll-out plan shall be prepared by the

marketing authorisation holder and be agreed by the Member State concerned. The

Member State may require the marketing authorisation holder to update the roll-out

plan.

When a Member State applies paragraph 1, it shall communicate it to the marketing

authorisation holder, together with the modalities referred to in paragraph 2, within one

year from the marketing authorisation for that medicinal product. The communication

under this paragraph shall contain explicit reference to this Article.

Where within 4 years after the marketing authorisation of the medicinal product has

been granted, the marketing authorisation holder has not made the medicinal product

available and has not supplied it continuously within that period in sufficient quantities

and in the presentations necessary to cover the needs of patients in a Member State that

made a request in accordance with paragraph 1, the market protection for that

medicinal product in accordance with Article 80(2), and, if applicable, the prolongation

of the market exclusivity in accordance with Article 72(2) of [revised Regulation

726/2004] shall not apply within that Member State.

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5a. The Member State shall make the information referred to in paragraph 5 publicly

available without undue delay. For medicinal products authorised in accordance with

[revised Regulation (EC) No 726/2004] the Member State shall also notify the Agency.

By way of derogation from Article 80(1), a marketing authorisation application may be

validated and assessed by the national competent authorities or the Agency six years

after the start of the data protection period of the reference medicinal product, where

the medicinal product is a generic or biosimilar medicinal product to a reference

medicinal product and where a Member State has made publicly available information

with regard to that reference medicinal product in accordance with paragraph 6. The

marketing authorisation validated and assessed in accordance with this paragraph shall

not be granted prior to the expiry of the regulatory data protection period.

This Article shall not affect the application of national legislation and procedures,

including pricing and reimbursment, public procurement and any other procedures,

aiming at making available and supplying the medicinal product concerned within their

territory at any time following the marketing authorisation.

This Article shall also not affect the right of marketing authorisation holders to make

available and supply the medicinal product concerned in a Member State by carrying

out the relevant procedures pursuant to national law, regardless of whether a request in

accordance with paragraph 1 has been made by that Member State.

In the course of the application of this Article, the Member States and the marketing

authorisation holder shall cooperate in good faith and undertake best efforts to making

available and suppling the medicinal product concerned in the concerned Member State.

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Member States representatives may request the Commission to discuss issues related to

the practical application of this Article in the Committee established by Council

Decision 75/320/EEC39 (‘Pharmaceutical Committee’). The Commission may invite

bodies responsible for health technology assessment as referred to in Regulation

(EU) 2021/2282 or national bodies responsible for pricing and reimbursement, as

required, to participate in the deliberations of the Pharmaceutical Committee.

The Pharmaceutical Committee may exchange views on national measures envisaged in

the event when the obligations under this Article are not met.

Marketing authorisation holders shall comply with the obligations set out in this Article,

except for exceptional and unforeseeable circumstances, including those related to

disruptions of supply, outside the marketing authorisation holder’s control, the

consequences of which could not have been avoided even if all reasonable measures had

been taken.

Article 57

Responsibility to report on public financial support

The marketing authorisation holder shall declare to the public any direct financial support

received from any public authority or publicly funded body, in relation to any activities for

the research and development of the medicinal product covered by a national or a centralised

marketing authorisation, irrespective of the legal entity that received that support.

Council Decision of 20 May 1975 setting up a pharmaceutical committee (OJ L 147, 9.6.1975, p.
23).

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Within 30 days after the marketing authorisation is granted the marketing authorisation holder

shall:

(a) draw up an electronic report listing:

(i)

the amount of financial support received and the date thereof;

(ii) the public authority or publicly funded body that provided the financial support

referred to in point (i);

(iii) the legal entity that received the support referred to in point (i).

(b) ensure that the electronic report is accurate and that it has been audited by an

independent external auditor;

(d) communicate the electronic link to such webpage to the competent authority of the

Member State or, where appropriate, to the Agency.

For the medicinal products authorised under this Directive, the competent authority of the

Member State shall communicate in a timely manner the electronic link to the Agency.

The marketing authorisation holder shall keep the electronic link up to date and, as necessary,

update the report annually.

The Member States shall take appropriate measures to ensure that paragraphs 1, 2 and 4 are

complied with by the marketing authorisation holder established in their country.

The Commission may adopt implementing acts to lay down the principles and format for the

information to be reported pursuant to paragraph 2. Those implementing acts shall be adopted

in accordance with the examination procedure referred to in Article 214(2).

Article 58

Traceability of substances used in the manufacture of medicinal products

The marketing authorisation holder shall, when necessary, ensure the traceability of an active

substance, starting material, excipient or any other substance intended or expected to be

present in a medicinal product at all stages of manufacturing and distribution.

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The marketing authorisation holder shall be able to identify any natural or legal person from

whom they have been supplied with an active substance, starting material, excipient or any

other substance intended or expected to be present in a medicinal product.

The marketing authorisation holder and its suppliers of an active substance, starting material,

excipient or any other substance used in the manufacturing of a medicinal product shall have

in place systems and procedures that allow for the information referred to in paragraph 2 to be

made available, upon request, to the competent authorities.

The marketing authorisation holder and its suppliers shall have in place systems and

procedures to identify the other natural or legal persons to whom products referred to in

paragraph 2 have been supplied. This information shall, upon request, be made available to

the competent authorities.

Article 59

Placing on the market of products with paediatric indications

Where medicinal products are authorised for a paediatric indication following completion of an

agreed paediatric investigation plan and those medicinal products have already been marketed with

other therapeutic indications, the marketing authorisation holder shall, within two years of the date

on which the paediatric indication is authorised, place the medicinal product on the market taking

into account the paediatric indication in all Member States where the medicinal product is already

placed on the market.

A register, coordinated by the Agency, and made publicly available, shall mention these deadlines.

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Article 60

Discontinuation of the placing on the market of paediatric products

If a medicinal product is authorised for a paediatric indication and the marketing authorisation

holder has benefited from rewards or incentives under Article 86 of this Directive or Article 93 of

[revised Regulation (EC) No 726/2004], and these periods of protection have expired, and if the

marketing authorisation holder intends to discontinue placing the medicinal product on the market,

the marketing authorisation holder shall transfer the marketing authorisation to a third party or

allow a third party, which has declared its intention to continue to place the medicinal product in

question on the market, to use the pharmaceutical, non-clinical and clinical documentation

contained in the file of the medicinal product on the basis of Article 14.

The marketing authorisation holder shall inform the competent authorities of its intention to

discontinue the placing on the market of the medicinal product no less than twelve months before

the discontinuation. The competent authorities shall make this fact publicly available.

Article 61

Liability of the marketing authorisation holder

The marketing authorisation shall not affect the civil and criminal liability of the marketing

authorisation holder.

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Chapter VI

Product information and labelling

Article 62

Summary of product characteristics

The summary of product characteristics shall contain the particulars listed in Annex V.

For marketing authorisations under Articles 9 and to 112 and subsequent variations to such

marketing authorisations, if one or more of the therapeutic indications, posologies,

pharmaceutical forms, methods or routes of administration or any other way in which the

medicinal product may be used are still covered by patent law or a supplementary protection

certificate for medicinal products at the time when the generic, or biosimilar, hybrid or

biohybrid medicinal product was marketed, the applicant for an marketing authorisation or

a variation of a marketing authorisation for a generic or, biosimilar, hybrid or biohybrid

medicinal product may request not to include this information in their marketing

authorisation, however all relevant safety information related to the safe use of the

medicinal product shall be included.

For all medicinal products, a standard text shall be included in the summary of product

characteristics expressly asking healthcare professionals to report any suspected adverse

reaction in accordance with the national reporting system referred to in Article 106(1).

Different ways of reporting, including electronic reporting, shall be available in compliance

with Article 106(1), second subparagraph.

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Article 63

General principles on package leaflet

A package leaflet shall be mandatory for medicinal products. The package leaflet shall be

made available by the marketing authorisation holder in the packaging in paper format

and electronically in accordance with the specifications, standards and format specified

by the implementing act pursuant to paragraph 6. The competent authorities shall make

publicly available the electronic package leaflet on their websites.

The package leaflet shall be written and designed in a clear and understandable way, enabling

users to act appropriately, when necessary with the help of healthcare professionals.

By derogation from paragraph 1, Member States may decide that the package leaflet shall

be made available by the marketing authorisation holder for specific categories of

medicinal products or for all medicinal products, in paper format or only electronically, or

both. In the absence of such specific rules in a Member State, a package leaflet in paper

format shall be included in the packaging of a medicinal product. If the package leaflet is only

made available electronically, the patient’s right to a printed copy of the package leaflet

should shall be guaranteed upon request and free of charge and it should shall be ensured that

the information in digital format is easily accessible to all patients. The marketing

authorisation holder shall be responsible for both preparing the electronic leaflet and

ensuring that the printed version of the package leaflet is readily available to the patient.

If a Member State decides that the package leaflet shall be only made available

electronically, it shall not preclude the marketing authorisation holder from providing

the package leaflet in paper format in addition to the electronic version on a voluntary

basis.

3a. The obligation to make available the package leaflet in paper format in the packaging in

a Member State shall not constitute a reason for the marketing authorisation holder to

refuse to supply the medicinal product on the market in that Member State.

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By derogation from paragraphs 1 and 2, where the information required under Articles 64 and

73 is directly conveyed on the outer packaging or on the immediate packaging, a package

leaflet shall not be required.

The Commission is empowered to adopt delegated acts in accordance with Article 215 to

amend paragraph 3 by making mandatory the electronic version of the package leaflet. That

delegated act shall also establish the patient’s right to a printed copy of the package leaflet

upon request and free of charge. The delegation of powers shall apply as of [OP please insert

the date = five years following 18 months after the date of entering into force of this

Directive].

The Commission shall [by 12 months after entry into force of the Directive] adopt

implementing acts in accordance with the examination procedure referred to in Article 214(2)

to:

(a) establish common standards and formats for the electronic version of the package

leaflet, the summary of product characteristics and the labelling, taking into account

available technologies;

(b) establish criteria for the provision of such information through secure digital

platforms of the competent authorities;

(c) set the necessary processes to validate the electronic version of the package leaflet

and make it available to patients;

(d) specify mandatory information on the packaging on how to access the electronic

version of the package leaflet;

(e) specify the details of implementing commonly recognised European global

antimicrobial resistance symbol as referred to in Article 69, in the section of the

package leaflet that contains specific information about the medicinal product

concerned, information on antimicrobial resistance and the importance of

appropriate use and disposal of antimicrobials.

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Where the package leaflet is made available electronically, the individual right to privacy

personal data protection shall be ensured in line with Regulation (EU) 2016/679 and

Directive 2002/58/EC. Any technology giving access to the information shall not allow the

identification or tracking of individuals, nor shall it be used for commercial purposes.

Article 64

Content of package leaflet

The package leaflet shall be drawn up in accordance with the summary of product

characteristics, referred to in Article 62(1) and shall include the particulars listed in Annex VI.

For all medicinal products, a standardised text shall be included, expressly asking patients to

communicate any suspected adverse reaction to their doctor, pharmacist, healthcare

professional or directly to the national reporting system referred to in Article 106(1), and

specifying the different ways of reporting available (electronic reporting, postal address or

others) in compliance with Article 106(1), second subparagraph.

The package leaflet shall reflect the results of consultations with target patient groups to

ensure that it is legible, clear and easy to use.

Article 65

Labelling of the outer packaging Content of labelling particulars

The outer packaging of medicinal products or, where there is no outer packaging, the

immediate packaging, with the exception of the packaging referred to in Article 66,

paragraphs 2 and 3, shall include the labelling particulars listed in Annex IV.

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The Commission is empowered to adopt delegated acts in accordance with Article 215 to:

(a) amend the list of labelling particulars set out in Annex IV in order to take account of

scientific progress or patient needs;

(b) supplement Annex IV by setting out a reduced list of mandatory labelling particulars

that shall appear on the outer packaging of multi-language, multi-country packages

that are also multi-lingual.

Article 66

Labelling of blister packs or small immediate packaging

The particulars laid down in Annex IV shall appear on immediate packagings other than those

referred to in the paragraphs 2 and 3.

The following particulars at least shall appear on immediate packagings that take the form of

blister packs and are placed in an outer packaging that complies with the requirements laid

down in Articles 65 and 73.

(a) the name of the medicinal product followed by its strength, if appropriate, and

pharmaceutical form; where the medicinal product contains up to three active

substances, the international non-proprietary name (INN) shall be included or, if

one does not exist, the common name;

(b) the name of the marketing authorisation holder placing the product on the market;

(d) the batch number.

The following particulars at least shall appear on small immediate packaging units on which

the particulars laid down in Articles 65 and 73 cannot be displayed, shall include at least the

following labelling particulars:

(a) the name of the medicinal product followed by its strength, if appropriate, and

pharmaceutical form and, if necessary, the route of administration; where the

medicinal product contains up to three active substances, the international non-

proprietary name (INN) shall be included or, if one does not exist, the common

name;

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(b) the method route of administration, if not already evident from the name or

pharmaceutical form of the medicinal product;

(d) the batch number;

(e) the contents by weight, by volume or by unit.

Article 67

Safety features

Medicinal products subject to prescription shall bear the safety features referred to in Annex

IV, unless they have been listed in accordance with the procedure referred to in paragraph 2,

second subparagraph, point (b).

Medicinal products not subject to prescription shall not bear the safety features referred to in

Annex IV, unless, by way of exception, they have been listed in accordance with the

procedure referred to in paragraph 2, second subparagraph, point (b).

The Commission shall adopt delegated acts in accordance with Article 215 to supplement

Annex IV by laying down detailed rules for the safety features.

Those delegated acts shall set out:

(a) the characteristics and technical specifications of the unique identifier of the safety

features referred to in Annex IV point (o) that enables the authenticity of medicinal

products to be verified and individual packs to be identified;

(b) the lists containing the medicinal products or product categories that, in the case of

medicinal products subject to prescription shall not bear the safety features, and in the

case of medicinal products not subject to prescription shall bear the safety features

referred to in Annex IV point (o);

rapid system for evaluating and deciding on such notification for the purpose of

applying point (b);

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(d) the modalities for the verification of the safety features referred to in Annex IV

point (o) by the manufacturers, wholesale distributors, pharmacists and natural or legal

persons authorised or entitled to supply medicinal products to the public and by the

competent authorities;

(e) provisions on the establishment, management and accessibility of the repositories

system in which information on the safety features, enabling the verification of the

authenticity and identification of medicinal products, as provided for in Annex IV

point (o), shall be contained.

The lists referred to in the second subparagraph, point (b), shall be established considering the

risk of falsification relating to the medicinal products or categories of medicinal products

concerned. To this end, at least the following criteria shall be applied:

(a) the price and sales volume of the medicinal product;

(b) the number and frequency of previous cases of falsified medicinal products being

reported within the Union and in third countries and the evolution of the number and

frequency of such cases to date;

(d) the severity of the conditions intended to be treated;

(e) other potential risks to public health.

The modalities referred to in the second subparagraph, point (d), shall allow the verification

of the authenticity of each supplied pack of the medicinal products bearing the safety features

referred to in Annex IV point (o) and determine the extent of such verification. When

establishing those modalities, the particular characteristics of the supply chains in Member

States, and the need to ensure that the impact of verification measures on particular actors in

the supply chains is proportionate, shall be taken into account.

For the purposes of the second subparagraph, point (e), the costs of the repositories system

shall be borne by the manufacturing marketing authorisation holders of medicinal products

bearing the safety features.

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When adopting delegated acts referred to in paragraph 2, the Commission shall take due

account of at least the following:

(a) the protection of personal data as provided for in Union law;

(b) the legitimate interests to protect information of a commercially confidential nature;

and

(d) the cost-effectiveness of the measures.

The competent authorities of the Member States shall notify the Commission of non-

prescription medicinal products that they judge to be at risk of falsification and may inform

the Commission of medicinal products that they deem not to be at risk of falsification in

accordance with the criteria set out in paragraph 2, second subparagraph, point (b).

Member States may, for the purposes of reimbursement or pharmacovigilance, extend the

scope of application of the unique identifier referred to in Annex IV point (o) to any

medicinal product subject to prescription or subject to reimbursement.

The competent authorities Member States may, for the purposes of reimbursement,

pharmacovigilance, pharmacoepidemiology or for data protection prolongation for market

launch to monitor any expected potential or actual shortage of a medicinal product, as

well as to assess the general supply situation to avoid shortages, use the information

contained in the repositories system referred to paragraph 2, second subparagraph, point (e).

Member States may, for the purposes of patient safety, extend the scope of application of the

anti-tampering device referred to in Annex IV to any medicinal product.

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Article 68

Labelling and instruction leaflet of radionuclides and radiopharmaceuticals

In addition to the rules laid down in this Chapter, the outer carton and the container of

medicinal products containing radionuclides shall be labelled in accordance with the

regulations for the safe transport of radioactive materials laid down by the International

Atomic Energy Agency. Moreover, the labelling shall comply with the provisions set out in

paragraphs 2 and 3.

The label on the shielding shall include the particulars laid down in Article 65. In addition, the

label on the shielding shall explain in full, the codings used on the vial and shall indicate,

where necessary, for a given time and date, the amount of radioactivity per dose or per vial

and the number of capsules, or, for liquids, the number of millilitres in the container.

In addition to the requirements of Article 66, Tthe vial shall be labelled with the following

information:

(a) the name or code of the medicinal product, including the name or chemical symbol of

the radionuclide;

(b) the batch identification and expiry date;

(d) the name and address of the manufacturer;

(e) the amount of radioactivity as specified in paragraph 2.

The competent authority marketing authorisation holder shall ensure that a detailed

instruction leaflet is enclosed with the packaging of radiopharmaceuticals, radionuclide

generators, radionuclide kits or radionuclide precursors. The text of this leaflet shall be

established in accordance with Article 64(1). In addition, the leaflet shall include any

precautions to be taken by the user and the patient during the preparation and administration

of the medicinal product and special precautions for the disposal of the packaging and its

unused contents.

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Article 69

Special information requirements for antimicrobials

The marketing authorisation holder shall ensure availability of educational material to

healthcare professionals, including through medical sales representatives as referred to in

Article 175(1), point (c), regarding the appropriate use of diagnostic tools, testing or other

diagnostic approaches related to antimicrobial-resistant pathogens, that may inform on the use

of the antimicrobial.

The marketing authorisation holder shall include in the beginning of the package leaflet of

antimicrobials a document section that contains the global antimicrobial resistance symbol

specific information about the medicinal product concerned and that is made available to the

patient in addition to the product leaflet (“awareness card”) and with information on

antimicrobial resistance and the importance the appropriate use and disposal of

antimicrobials.

In the case of electronic version of the package leaflet, the information referred to in the

previous subparagraph shall be made available to patients electronically in a distinct

and immediately visible way.

Member States may decide that the awareness card shall be made available in paper format or

electronically, or both. In the absence of such specific rules in a Member State, an awareness

card in paper format shall be included in the packaging of an antimicrobial.

The text of the awareness card shall be aligned with Annex VI.

Article 70

Legibility

The package leaflet and labelling particulars referred to in this Chapter shall be easily legible,

clearly comprehensible and indelible.

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Article 71

Accessibility for persons with disabilities

The name of the medicinal product, followed by its strength, if appropriate, and pharmaceutical

form, if appropriate, shall also be expressed in Braille format on the packaging. The marketing

authorisation holder shall ensure that the package leaflet referred to in Article 63 is made available

free of charge upon request from patients' organisations in formats appropriate for persons with

disabilities, including blind and partially-sighted persons.

Article 72

Member States labelling requirements

Notwithstanding Article 778 Member States may require the use of certain forms of labelling

of the medicinal product making it possible to ascertain:

(a) the price of the medicinal product;

(b) the reimbursement conditions of social security organisations;

(d) authenticity and identification in accordance with Article 67(5);

(e) the identity of the medicinal product in accordance with national requirements,

including for statistical reasons.

For medicinal products for which a centralised marketing authorisation as referred to in

Article 5 has been granted, Member States shall, when applying this Article, observe consider

the detailed guidance referred to in Article 77.

Article 73

Symbols and pictogram

The outer packaging and the package leaflet may include symbols or pictograms designed to clarify

certain information set out in Articles 64(1), and 65 and 66 and other information compatible with

the summary of product characteristics that is useful for the patient, to the exclusion of any element

of a promotional nature.

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Article 74

Requirements on languages

The particulars for labelling listed in Articles 64 and to 656, shall appear in an official

language or official languages of the Member State where the medicinal product is placed on

the market, as specified, for the purposes of this Directive, by that Member State, as well as

in the English language in the electronic version of the package leaflet.

Paragraph 1 shall not prevent those particulars from being indicated appearing in several

languages, provided that the same particulars appear in all the languages used.

The package leaflet must be clearly legible in an official language or official languages of the

Member State where the medicinal product is placed on the market, as specified, for the

purposes of this Directive, by that Member State.

The competent authorities of the Member State may also grant a full or partial exemption to

the obligation that the labelling and the package leaflet must be in an official language or

official languages of the Member State where the medicinal product is placed on the market,

as specified, for the purposes of this Directive, by that Member State. For the purpose of

multi-language or multi-country packages, Member States may allow the use on the

labelling and package leaflet of an official language of the Union that is commonly

understood in the Member States where the multi-language or multi-country package is

marketed.

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Article 75

Member States exemptions from requirements for labelling and package leaflet

The competent authorities of the Member States may, subject to measures they consider necessary

to safeguard public health, grant an exemption to the obligation that the particulars required in

Articles 64, and 65 and 66 should appear on the labelling and in the package leaflet in the following

cases:

(a) where the medicinal product is not intended to be delivered directly to the patient;

(b) where there are problems in respect of the availability of the medicinal product;

in case of multilingualmulti-language or multi-country packages or package leaflets;

(d) in the context of a public health emergency;

(e) to facilitate access to medicines in Member States.

Article 76

Approval of the labelling and package leaflet information

One or more mock-ups of the outer packaging and the immediate packaging of a medicinal

product, together with the package leaflet, shall be submitted to the competent authorities for

authorising marketing when the marketing authorisation is requested. The results of

assessments carried out in cooperation with target patient groups shall also be provided to the

competent authority.

The competent authority shall refuse the marketing authorisation if the labelling or the

package leaflet do not comply with the provisions of this Chapter or if they are not in

accordance with the particulars listed in the summary of product characteristics.

All proposed changes to an aspect of the labelling or the package leaflet covered by this

Chapter and not connected with the summary of product characteristics shall be submitted to

the competent authorities. If the competent authorities have not opposed a proposed change

within 90 days following the introduction submission of the request, the applicant may put

the change into effect.

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The fact that the competent authority does not refuse a marketing authorisation pursuant to

paragraph 2 or a change to the labelling or the package leaflet pursuant to paragraph 3 does

not alter the general legal liability of the manufacturer and the marketing authorisation holder.

Article 77

Guidance on labelling particulars

In consultation with the Member States and the parties concerned, the Commission shall draw up

and publish detailed guidance concerning in particular:

(a) the wording of certain special warnings for certain categories of medicinal products;

(b) the particular information needs relating to non-prescription medicinal products;

(d) the methods for the identification and authentication of medicinal products;

(e) the list of excipients that must featurethat may feature on the labelling of medicinal products

and the way in which these excipients must be indicated the information for specific

excipients that feature on the labelling of medicinal products;

(f)

harmonised provisions for the implementation of Article 72.;

(g) harmonised use of symbols, pictograms and abbreviations.

Article 78

Placing on the market of labelled medicinal products

Member States may not prohibit or impede the placing on the market of medicinal products within

their territory on grounds connected with labelling or the package leaflet where these comply with

the requirements of this Chapter.

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Article 79

Non-compliance with the requirements for labelling and package leaflet

Where the provisions of this Chapter are not complied with, and a notice served on the marketing

authorisation holder concerned has remained without effect, the competent authorities of the

Member States may suspend the marketing authorisation, until the labelling and the package leaflet

of the medicinal product in question have been made to comply with the requirements of this

Chapter.

Chapter VII

Regulatory protection, unmet medical needs and rewards for

paediatric medicinal products

Article 80

Regulatory data and market protection

The data referred to in Annex I, originally submitted with the view to obtaining a marketing

authorisation shall not be referred to by another applicant for a subsequent marketing

authorisation during the period determined in accordance with Article 81 (‘regulatory data

protection period’).eight years from the date when the marketing authorisation for that

medicinal product was granted in accordance with Article 6(2), except when one

additional year of data protection is granted in accordance with Article 41 (1) of [revised

Regulation (EC) No 726/2004] (‘regulatory data protection period’). For marketing

authorisations that belong to the same global marketing authorisation in accordance

with Article 5(2) the period of data protection shall start from the date when the initial

marketing authorisation was granted in the Union.

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A medicinal product concerned by a subsequent marketing authorisation referred to in

paragraph 1 shall not be placed on the market for a period of two one years after the expiry of

the relevant regulatory data protection (‘regulatory market protection period’). periods

referred to in Article 81. This period may be prolonged in accordance with Article 81.

The period shall be extended to three years if, during the regulatory data protection

period referred to in paragraph 1, the marketing authorisation holder obtains an

authorisation for one or more new therapeutic indications which, during the scientific

evaluation prior to their authorisation and based on supporting data submitted by the

marketing authorisation holder, are held to bring a significant clinical benefit in

comparison with existing therapies.

By way of derogation from paragraph 1, the marketing authorisation holder concerned may

grant the marketing authorisation applicant for another marketing authorisation a letter of

access to its data submitted under Annex I, as referred to in Article 14.

By way of derogation from the paragraphs 1 and 2, when a compulsory licence has been

granted by a relevant authority in the Union to a party licensee under conditions laid out in

Union or national law to address a public health emergency, the relevant data and market

protection shall be suspended with regard to that party licensee insofar as the compulsory

licence requires, and during for the duration and the territory of the Member States for

which period of the compulsory licence has been granted.

The data protection period set out to in paragraph 1 shall also apply in Member States where

the medicinal product is not authorised or is no longer authorised.

5a. National competent authorities shall make on their website available the list of medicinal

products they have granted a national marketing authorisation and are protected by

regulatory data protection, indicating the applicable prolongation in accordance with

Article 81. The Agency shall compile and publish a list of hyperlinks to the websites

referred to in this paragraph.

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Article 81

Additional Rregulatory data market protection periods

The regulatory data protection period shall be six seven years from the date when the

marketing authorisation for that medicinal product was granted in accordance with Article

6(2). For marketing authorisations that belong to the same global marketing authorisation the

period of data protection shall start from the date when the initial marketing authorisation was

granted in the Union.

Subject to a scientific evaluation by the relevant competent authority, the The regulatory

data market protection period referred to in Article 80 paragraph 21 shall be prolonged by 12

monthsthe following periods by:

(a) 12 months, where the marketing authorisation applicant demonstrates at the time

of the initial marketing authorisation application that the medicinal product

addresses an unmet medical need as referred to in Article 83;

(b) 12 months for medicinal products containing a new active substance, where the

marketing authorisation applicant demonstrates the fulfillment of all the following

conditions:

the clinical trials supporting the initial marketing authorisation application

use, where possible and appropriate, a relevant and evidence-based

comparator in accordance with the scientific advice provided by the Agency;

ii)

clinical trials evaluating the efficacy of the medicinal product and used for

the marketing authorisation were conducted in several more than one

Member States;

iii) the marketing authorisation applicant demonstrates that the marketing

authorisation application has been first submitted to the competent authority

in the Union or has been submitted no later than 90 days after the submission

of the application for the first marketing authorisation outside the Union.

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In the case of prolongation of data the regulatory market protection in accordance with

paragraph 2(a), the applicant shall demonstrate that the improvement in efficacy or

safety of the medicinal product meets the conditions referred to in Article 83 paragraph

1 (a) or (b); in case of claiming to have met the condition referred to in Article 83

paragraph 1 (b) the applicant shall demonstrate meeting this condition with data from

clinical trials that use, where possible and appropriate, a relevant and evidence-based

comparator.

(a) 24 months, where the marketing authorisation holder demonstrates that the conditions

referred to in Article 82(1) are fulfilled within two years, from the date when the

marketing authorisation was granted or, within three years from that date for any of the

following entities:

(i)

SMEs within the meaning of Commission Recommendation 2003/361/EC;

(ii) entities not engaged in an economic activity (‘not-for-profit entity’); and

(iii) undertakings that, by the time of granting of a marketing authorisation, have

received not more than five centralised marketing authorisations for the

undertaking concerned or, in the case of an undertaking belonging to a group, for

the group of which it is part, since the establishment of the undertaking or the

group, whichever is earliest.

(b) six months, where the marketing authorisation applicant demonstrates at the time of the

initial marketing authorisation application that the medicinal product addresses an

unmet medical need as referred to in Article 83;

trials supporting the initial marketing authorisation application use a relevant and

evidence-based comparator in accordance with scientific advice provided by the

Agency;

(d) 12 months, where the marketing authorisation holder obtains, during the data protection

period, an authorisation for an additional therapeutic indication for which the marketing

authorisation holder has demonstrated, with supporting data, a significant clinical

benefit in comparison with existing therapies.

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In the case of a conditional marketing authorisation granted in accordance with Article 19 of

[revised Regulation (EC) No 726/2004] the prolongation referred to in the first subparagraph,

point (ba), shall only apply if,:

- within four years of the granting of the conditional marketing authorisation, the medicinal

product has been granted a marketing authorisation in accordance with Article 19(7) of

[revised Regulation (EC) No 726/2004, and;

- in the case of medicinal products referred to in Article 83, paragraph 1(b), the

studies referred to in Article 19(4) of [revised Regulation (EC) No 726/2004] shall

include clinical trials that use, where possible and appropriate, a relevant and

evidence-based comparator.

The prolongation referred to in the first subparagraph, point (d), may only be granted once.

The cumulative duration of data protection for a medicinal product shall not exceed

eight years from the date when the initial marketing authorisation was granted, except

when one additional year of data protection is granted in accordance with Article 41 (1)

of [revised Regulation (EC) No 726/2004].

2a. The regulatory market protection period shall be extended by an additional year if,

during the regulatory data protection period referred to in Article 80 paragraph 1, the

marketing authorisation holder obtains an authorisation for one or more new

therapeutic indications which, during the scientific evaluation prior to their

authorisation and based on supporting data submitted by the marketing authorisation

holder, are held to bring a significant clinical benefit in comparison with existing

therapies.

2b. The cumulative duration of the regulatory market protection for a medicinal product

shall not exceed two years from the date when the regulatory data protection expires,

except when one additional year of the regulatory market protection is granted in

accordance with paragraph 2a.

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The Agency shall set the scientific guidelines referred to in paragraph 2, point (cb) (i), on

criteria for proposing a comparator for a clinical trial, taking into account the results of the

consultation of the Commission and the authorities or bodies involved in the mechanism of

consultation referred to in Article 162 of [revised Regulation (EC) No 726/2004], in

particular bodies responsible for health technology assessment as referred to in

Regulation (EU) 2021/2282.

Article 82

Prolongation of the data protection period for medicinal products supplied in Member States

The prolongation of the data protection period referred to in Article 81(2), first subparagraph,

point (a), shall only be granted to medicinal products if they are released and continuously

supplied into the supply chain in a sufficient quantity and in the presentations necessary to

cover the needs of the patients in the Member States in which the marketing authorisation is

valid.

The prolongation referred to in the first subparagraph shall apply to medicinal products that

have been granted a centralised marketing authorisation, as referred to in Article 5 or that

have been granted a national marketing authorisation through the decentralised procedure, as

referred to in Chapter III, Section 3.

To receive a prolongation referred to in Article 81(2), first subparagraph, point (a), the

marketing authorisation holder shall apply for a variation of the relevant marketing

authorisation.

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The application for a variation shall be submitted between 34 and 36 months after the date

when the initial marketing authorisation was granted, or for entities referred to in Article

81(2), first subparagraph, point (a), between 46 and 48 months, after that date.

The application for a variation shall contain documentation from the Member States in which

the marketing authorisation is valid. Such documentation shall:

(a) confirm that the conditions set out in paragraph 1 have been satisfied in their territory;

(b) waive the conditions set out in paragraph 1 in their territory for the purpose of the

prolongation.

Positive decisions adopted in accordance with Articles 2 and 6 of Council Directive

89/105/EEC40 shall be considered equivalent to a confirmation referred to in the third

subparagraph, point (a).

To receive the documentation referred to in paragraph 2, third subparagraph, the marketing

authorisation holder shall make a request to the relevant Member State. Within 60 days from

the request of the marketing authorisation holder, the Member State shall issue a confirmation

of compliance or, a reasoned statement of non-compliance or alternatively provide a statement

of non-objection to prolong the period of regulatory data protection pursuant to this Article.

In cases where a Member State has not replied to the application of the marketing

authorisation holder within the deadline referred to in paragraph 3, it shall be considered that

a statement of non-objection has been provided.

Council Directive 89/105/EEC of 21 December 1988 relating to the transparency of measures
regulating the prices of medicinal products for human use and their inclusion in the scope of national
health insurance systems (OJ L 40, 11.2.1989, p. 8).

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For medicinal products granted a centralised marketing authorisation the Commission shall

vary the marketing authorisation pursuant to Article 47 of [revised Regulation (EC) No

726/2004] to prolong the data protection period. For medicinal products granted a marketing

authorisation in accordance with the decentralised procedure, the competent authorities of the

Member States shall vary the marketing authorisation pursuant to Article 92 to prolong the

data protection period.

Member States representatives may request the Commission to discuss issues related to the

practical application of this Article in the Committee established by Council Decision

75/320/EEC41 (‘Pharmaceutical Committee’). The Commission may invite bodies responsible

for health technology assessment as referred to in Regulation (EU) 2021/2282 or national

bodies responsible for pricing and reimbursement, as required, to participate in the

deliberations of the Pharmaceutical Committee.

The Commission, based on the experience of Member States and relevant stakeholders, may

adopt implementing measures relating to the procedural aspects outlined in this Article and

regarding the conditions mentioned in paragraph 1. Those implementing acts shall be adopted

in accordance with the procedure referred to in Article 214(2).

Article 83

Medicinal products addressing an unmet medical need

A medicinal product shall be considered as addressing an unmet medical need if at least one

of its therapeutic indications relates to a life threatening or severely debilitating disease and

either of the following conditions are met:

(a) there is no medicinal product authorised in the Union for such disease; or, where despite

medicinal products being authorised for such disease in the Union, the disease is

associated with a remaining high morbidity or mortality

Council Decision of 20 May 1975 setting up a pharmaceutical committee (OJ L 147, 9.6.1975, p. 23).

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(b) the use of the medicinal product for such a disease results in clinically relevant

improvement in efficacy, or in safety with at least comparable efficacy, in

comparison with existing medicinal products or other methods of diagnosis,

prevention or treatment authorised in the Union a meaningful reduction in disease

morbidity or mortality for the relevant patient population.

Designated orphan medicinal products referred to in Article 67 of [revised Regulation (EC)

No 726/2004] shall be considered as addressing an unmet medical need.

Where tThe Agency shall adopts scientific guidelines for to support the application of this

Article. To this end, it shall consult the Commission and the authorities or bodies referred to

in Article 162 of [revised Regulation (EC) No 726/2004].

Article 84

Data protection for repurposed medicinal products

A regulatory data protection period of four years shall be granted for a medicinal product with

respect to a new therapeutic indication not previously authorised in the Union for the active

substance(s), provided that:

(a) adequate non-clinical or clinical studies and, where relevant, non-clinical

studies/tests were carried out in relation to the therapeutic indication demonstrating that

it is of significant clinical benefit, and

(b) the medicinal product is authorised in accordance with Articles 9 to 12 and has not

previously benefitted from data protection, or 25 years have passed since the granting of

the initial marketing authorisation of the medicinal product concerned.

The data protection period referred to in paragraph 1 may only be granted once for any given

medicinal product.

During the data protection period referred to in paragraph 1, the marketing authorisation shall

indicate that the medicinal product is an existing medicinal product authorised in the Union

that has been authorised with an additional therapeutic indication.

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Article 85

Exemption to the protection of intellectual property rights

The protection provided by pPatent rights, or supplementary protection certificates of

medicinal products under the [Regulation (EC) No 469/2009 - OP please replace reference

by new instrument when adopted] shall not be regarded as infringed when the necessary

studies, trials and other activities are conducted a reference medicinal product is used for

the purposes of:

(a) studies, trials and other activities conducted to generate data for an application for:

(i)

obtaining a marketing authorisation of medicinal products, in particular of generic,

biosimilar, hybrid or bio-hybrid medicinal products and for subsequent variations;

(aa)(ii) conducting health technology assessment as defined in Regulation (EU) 2021/2282;

(ab)(iii) obtaining pricing and reimbursement approval;

(ac) complying with subsequent practical requirements associated with activities

referred to in points (a)-(ab).

(ad) submitting an application on procurement tenders, in compliance with Union and

national law, to the extent that it does not entail the sale or offering for sale or

marketing of the medicinal product concerned during the protection period

provided by patent rights or supplementary protection certificate.

(b)

Tthe activities conducted exclusively for the purposes set out the first

subparagraph in point (a), may cover, where relevant, the submission of the application for

a marketing authorisation and the offer, manufacture, sale, supply, storage, import, use and

purchase of patented medicinal products or processes, including by third party suppliers and

service providers.

Decisions adopted concerning the activities referred to in paragraph 1 shall not be

considered as infringing intellectual property rights, within the meaning of that

paragraph.

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This exception provided for in this Article shall not cover the placing on the market of the

medicinal products resulting from such activities.

Article 86

Rewards for paediatric medicinal products

Where an application for marketing authorisation, includes the results of all studies conducted

in compliance with an agreed paediatric investigation plan, the holder of the patent or

supplementary protection certificate shall be entitled to a six-month extension of the period

referred to in Article 13, paragraphs 1 and 2 of [Regulation (EC) No 469/2009 - OP please

replace reference by new instrument when adopted].

The first subparagraph shall also apply where completion of the agreed paediatric

investigation plan fails to lead to the authorisation of a paediatric indication, but the results of

the studies conducted are reflected in the summary of product characteristics and, if

appropriate, in the package leaflet of the medicinal product concerned.

The inclusion in a marketing authorisation of the statement referred to in Article 49(2) of this

Directive or in Article 90(2) of [revised Regulation (EC) No 726/2004] shall be used for the

purposes of applying paragraph 1.

Where the procedures laid down in Chapter III, Sections 3 and 4, have been used, the six-

month extension of the period referred to in paragraph 1 shall be granted only if the product is

authorised in all Member States.

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In the case of an application for new paediatric therapeutic indications, including paediatric

indications, new pharmaceutical forms, new strengths and new routes of administration of

authorised medicinal products for a medicinal product which are is protected either by a

supplementary protection certificate under [Regulation (EC) No 469/2009 - OP please replace

reference by new instrument when adopted], or by a patent which qualifies for the granting of

the supplementary protection certificate which leads to the authorisation of a new paediatric

indication, paragraphs 1, 2 and 3 shall not apply if the applicant applies for, and obtains, a

one-year extension of the period of marketing market protection for the medicinal product

concerned, on the grounds that this new paediatric indication brings a significant clinical

benefit in comparison with existing therapies, in accordance with Article 8110(2a), first

subparagraph, point (d).

Chapter VIII

Post-marketing authorisation measures

Article 87

Imposed post-authorisation studies

After the granting of a marketing authorisation, the competent authority of the Member State

may impose an obligation on the marketing authorisation holder:

(a) to conduct a post-authorisation safety study if there are concerns about the risks of an

authorised medicinal product. If the same concerns apply to more than one medicinal

product, the competent authority of the Member State shall, following consultation with

the Pharmacovigilance Risk Assessment Committee, encourage the marketing

authorisation holders concerned to conduct a joint post-authorisation safety study;

(b) to conduct a post-authorisation efficacy study when the understanding of the disease or

the clinical methodology indicate that previous efficacy evaluations might have to be

revised significantly. The obligation to conduct the post-authorisation efficacy study

shall be based on the delegated acts adopted pursuant to Article 88 while taking into

account the scientific guidance referred to in Article 123.

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(ba) to conduct any other post-authorisation studies to improve the safe and effective

use of the medicinal product, including treatment optimisation based on clinical

experience;

monitoring data or information on use, if there are concerns about the risks to the

environment or public health, including antimicrobial resistance, due to an authorised

medicinal product, or other medicinal products containing the same related active

substance;

If the same concerns apply to more than one medicinal product, and post-authorisation

studies are considered necessary, the competent authority of Member State shall, following

consultation with the Agency, encourage the marketing authorisation holders concerned to

conduct a joint post-authorisation environmental risk assessment study.

The imposition of such an obligation shall be duly justified, notified in writing, and shall

include the objectives and timeframe for submission and conduct of the study.

The competent authority of the Member State shall provide the marketing authorisation holder

with an opportunity to present written observations in response to the imposition of the

obligation within a time limit which it shall specify, if the marketing authorisation holder so

requests within 30 days of receipt of the written notification of the obligation.

On the basis of the written observations submitted by the marketing authorisation holder, the

competent authority of the Member State shall withdraw or confirm the obligation. Where the

competent authority of the Member State confirms the obligation, the marketing authorisation

shall be varied to include the obligation as a condition of the marketing authorisation and,

where appropriate, the risk management system shall be updated accordingly.

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Article 88

Delegated acts on post-authorisation efficacy studies

In order to determine the situations in which post-authorisation efficacy studies may be

required under Articles 44 and 87, the Commission may adopt, by means of delegated acts in

accordance with Article 215, measures supplementing the provisions in Articles 44 and 87.

When adopting such delegated acts, the Commission shall act in accordance with the

provisions of this Directive.

Article 89

Recording of conditions related to marketing authorisations

The marketing authorisation holder shall incorporate any safety or efficacy conditions referred

to in Articles 44, 45 and 87 paragraph 1, points (a), (b) and (ba) in the risk management

system.

The Member States shall inform the Agency of the marketing authorisations that they have

granted subject to conditions pursuant to Articles 44, 45 and of any obligations imposed in

accordance with Article 87.

Article 90

Update of marketing authorisation related to scientific and technological progress developments

After a marketing authorisation has been granted in accordance with Chapter III, the

marketing authorisation holder shall, in respect of the methods of manufacture and control

stated in the application for that marketing authorisation, take account of scientific and

technical progress and introduce any changes that may be required to enable the medicinal

product to be manufactured and controlled by means of generally accepted scientific methods.

Those changes shall be subject to the approval of the competent authority of the Member

State concerned.

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The marketing authorisation holder shall without undue delay provide the competent authority

of the Member State with any new information that might entail the amendment of the

particulars or documentations referred to in Articles 6, 9 to 13, 62, 41(5), Annex I or Annex

II.

In particular, the marketing authorisation holder shall without undue delay inform the

competent authority of the Member State of any prohibition or restriction imposed on the

marketing authorisation holder or any entity in contractual relationship with the marketing

authorisation holder by the competent authorities of any country in which the medicinal

product is marketed and of any other new information that might influence the evaluation of

the benefits and risks of the medicinal product concerned. The information shall include both

positive and negative results of clinical trials or other studies in all therapeutic indications and

populations, whether or not included in the marketing authorisation, as well as data on the use

of the medicinal product where such use is outside the terms of the marketing authorisation.

The marketing authorisation holder shall ensure that the terms of the marketing authorisation

including the summary of product characteristics, the labelling and package leaflet are kept up

to date with current scientific knowledge, including the conclusions of the assessment and

recommendations made publicly available by means of the European medicines web-portal

set up in accordance with Article 104 of [revised Regulation (EC) No 726/2004].

The competent authority of the Member State may at any time request the marketing

authorisation holder to submit data demonstrating that the benefit-risk balance remains

favourable. The marketing authorisation holder shall answer fully and within the time limit

set, any such request. The marketing authorisation holder shall also respond fully and within

the time limit set to any request of a competent authority regarding the implementation of any

measures previously imposed, including risk minimisation measures.

The competent authority of the Member State may at any time ask the marketing authorisation

holder to submit a copy of the pharmacovigilance system master file. The marketing

authorisation holder shall submit that copy at the latest seven days after receipt of the request.

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The marketing authorisation holder shall also respond fully and within the time limit set to

any request of a competent authority regarding the implementation of any measures

previously imposed with regard to risks to the environment or public health, including

antimicrobial resistance.

Article 91

Update of risk management plans

The marketing authorisation holder of a medicinal product referred to in Articles 9 and 11,

who did not submit a risk management plan in accordance with Article 21 shall submit to

the competent authorities of the Member States concerned a risk management plan and a

summary thereof, where the marketing authorisation for the reference medicinal product is

withdrawn but the marketing authorisation for the medicinal product referred to in Articles 9

and 11 is maintained.

The risk management plan and the summary thereof shall be submitted to the competent

authorities of the Member States concerned within 60 days of the withdrawal of the marketing

authorisation for the reference medicinal product by means of a variation.

The competent authority of the Member State may impose an obligation on a marketing

authorisation holder for a medicinal product referred to Articles 9 and 11 to submit a risk

management plan and summary thereof where:

(a) additional risk minimisation measures have been imposed concerning the reference

medicinal product; or

(b) it is justified on pharmacovigilance grounds.

In the case referred to in paragraphs 1 and 2, point (a), the risk management plan shall be

aligned with the risk management plan for the reference medicinal product.

The imposition of the obligation referred to in paragraph 3 2 shall be duly justified in writing,

notified to the marketing authorisation holder and shall include the deadline for submission of

the risk management plan and the summary by means of a variation.

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Article 92

Variation of marketing authorisation

An application for variation of a marketing authorisation by the marketing authorisation

holder shall be made electronically in the formats made available by the Agency, unless the

variation is an update by the marketing authorisation holder of their information held in a

database.

Variations shall be classified in different categories depending on the level of risk to public

health and the potential impact on the quality, safety and efficacy of the medicinal product

concerned. Those categories shall range from changes to terms of the marketing authorisation

that have the highest potential impact on the quality, safety or efficacy of the medicinal

product, to changes that have no or minimal impact thereon and to administrative changes.

The procedures for examination of applications for variations shall be proportionate to the risk

and impact involved. Those procedures shall range from procedures that allow

implementation only after approval based on a complete scientific assessment to procedures

that allow immediate implementation and subsequent notification by the marketing

authorisation holder to the competent authority. Such procedures may also include updates by

the marketing authorisation holder of their information held in a database.

The Commission is empowered to adopt delegated acts in accordance with Article 215 to

supplement this Directive by establishing the following:

(a) the categories referred to in paragraph 2 in which variations shall be classified;

(b) rules for the examination of applications for variations to the terms of marketing

authorisations, including procedures for updates through a database;

terms of the same marketing authorisation and for the same change to the terms of

several marketing authorisations;

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(d) specifying exemptions to the variation procedures where the update of information in

the marketing authorisation referred to in Annex I may be directly implemented;

(e) the conditions and procedures for cooperation with competent authorities of third

countries or international organisations on examination of applications for variations to

the terms of marketing authorisation.

Article 93

Variation of marketing authorisation under the decentralised or mutual recognition procedure

Any application by the marketing authorisation holder to vary a marketing authorisation that

has been granted in accordance with the provisions of Chapter III, Sections 3 and 4, shall be

submitted to all the Member States that have previously authorised the medicinal product

concerned under the procedure set out in Article 34 or 36. The same shall apply where the

initial marketing authorisations were granted through separate procedures.

In case of arbitration submitted to the Commission, the procedure laid down in Articles 41

and 42 shall apply by analogy to variations made to marketing authorisations.

Article 93a

Variation based on additional evidence

The competent authority of the Member State may consider and decide upon additional

evidence available, independently from the data submitted by the marketing authorisation

holder. On that basis, if the additional evidence has an impact on the benefit-risk balance of a

medicinal product, the competent authorities may recommend that the summary of product

characteristics is updated. In this case the marketing authorisation holder shall submit to the

competent authority an appropriate application for a variation, including an updated

summary of product characteristics. For medicinal products authorised in accordance with

Articles 34 or 36, the reference Member State and all concerned member States shall be

involved.

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Article 94

Variation of marketing authorisations on the basis of paediatric studies

On the basis of relevant paediatric clinical studies received in accordance with Article 45(1)

of Regulation (EC) No 1901/2006 of the European Parliament and of the Council42, the

competent authorities of the Member States may vary the marketing authorisation of the

medicinal product concerned accordingly and consequently the marketing authorisation

holder shall update the summary of product characteristics and package leaflet of the

medicinal product concerned. The competent authorities shall exchange information regarding

the studies submitted and, as appropriate, their implications for any marketing authorisations

concerned..

The activities pursuant to paragraph 1 shall be concluded within five years from [OP please

insert the date = 18 36 months after the date of entering into force of this Directive].

When a medicinal product has been authorised under the provisions of Chapter III, on the

basis of the information received in accordance with Article 91 of [revised Regulation (EC)

No 726/2004], the competent authorities of the Member States may vary the marketing

authorisation of the medicinal product concerned accordingly and update the summary of

product characteristics and package leaflet.

The Member States shall exchange information regarding the paediatric studies submitted

and, as appropriate, their implications for any marketing authorisations concerned.

The Agency shall coordinate the exchange of information.

Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006
on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive
2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 378, 27.12.2006, p. 1).

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Article 95

Union interest referral procedure

The Member States or the Commission shall, in specific cases where the interests of the

Union are involved, refer the matter to the Committee for Medicinal Products for Human Use

for the application of the procedure laid down in Articles 41 and 42 before any decision is

reached on an application for a marketing authorisation or on the suspension or revocation of

a marketing authorisation, or on any other variation of the marketing authorisation that

appears necessary. The Member States and the Commission shall take due account of

consider any requests by the applicant or the marketing authorisation holder to initiate such

a referral.

Where the referral results from the evaluation of data relating to pharmacovigilance of an

authorised medicinal product, the matter shall be referred to the Pharmacovigilance Risk

Assessment Committee and Article 115(2) may be applied. The Pharmacovigilance Risk

Assessment Committee shall issue a recommendation according to the procedure laid down in

Article 41. The final recommendation shall be forwarded to the Committee for Medicinal

Products for Human Use or to the coordination group, as appropriate, and the procedure laid

down in Article 115 shall apply.

However, where one of the criteria listed in Article 114(1) is met, the procedure laid down in

Articles 114, 115 and 116 shall apply.

The Member State concerned or the Commission shall clearly identify the question that is

referred to the Committee for consideration and shall inform the applicant or the marketing

authorisation holder.

The Member States and the applicant or the marketing authorisation holder shall supply the

Committee with all available information relating to the matter in question.

Where the referral to the Committee concerns a range of medicinal products or a therapeutic

class, the Agency may limit the procedure to certain specific parts of the authorisation.

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In that event, Article 93 shall apply to those medicinal products only if they were covered by

the authorisation procedures referred to in Chapter III, Sections 3 and 4.

Where the scope of the procedure initiated under this Article concerns a range of medicinal

products or a therapeutic class, medicinal products covered by a centralised marketing

authorisation that belong to that range or class shall also be included in the procedure.

Without prejudice to paragraph 1, a Member State may, where urgent action is necessary to

protect public health at any stage of the procedure, suspend the marketing authorisation and

prohibit the use of the medicinal product concerned on its territory or take other risk

minimisation measures until a definitive decision is adopted. It shall inform the

Commission, the Agency and the other Member States, no later than the following working

day, of the reasons for its action.

Where the scope of the procedure initiated under this Article, as determined in accordance

with paragraph 2, includes medicinal products covered by a centralised marketing

authorisation, the Commission may, where urgent action is necessary to protect public health,

at any stage of the procedure suspend the marketing authorisations and prohibit the use of the

medicinal products concerned or take risk minimisation measures until a definitive decision

is adopted. The Commission shall inform the Agency and the Member States no later than the

following working day of the reasons for its action.

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Chapter IX

Pharmacovigilance

Section 1

General provisions

Article 96

Member State pharmacovigilance system

Member States shall operate a pharmacovigilance system for the fulfilment of their

pharmacovigilance tasks and their participation in the Union pharmacovigilance activities.

The pharmacovigilance system shall be used to collect information on the risks of medicinal

products as regards health of the patients or the public. That information shall in particular

refer to adverse reactions in human beings, arising from use of the medicinal product within

the terms of the marketing authorisation as well as from use outside the terms of the

marketing authorisation, and to adverse reactions associated with occupational exposure.

Member States shall, by means of the pharmacovigilance system referred to in paragraph 1,

evaluate all information scientifically, consider options for risk minimisation and prevention

and take regulatory action concerning the marketing authorisation as necessary. They shall

perform a regular audit of their pharmacovigilance system and take corrective actions if

necessary.

Each Member State shall designate a competent authority for the performance of

pharmacovigilance tasks.

The Commission may request the Member States to participate, under the coordination of the

Agency, in international harmonisation and standardisation of technical measures in relation

to pharmacovigilance.

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Article 97

Member State responsibilities for pharmacovigilance activities

The Member States shall:

(a) take all appropriate measures to encourage patients, doctors, pharmacists and other

healthcare professionals to report suspected adverse reactions to the competent authority

of the Member State and may involve organisations representing consumers, patients

and healthcare professionals for those tasks where appropriate;

(b) facilitate patient reporting through the provision of alternative reporting formats in

addition to web-based formats;

evaluation of suspected adverse reaction reports;

(d) ensure that the public is given important information on pharmacovigilance concerns

relating to the use of a medicinal product in a timely manner through publication on the

web-portal and through other means of publicly available information as necessary;

(e) ensure, through the methods for collecting information and where necessary through the

follow-up of suspected adverse reaction reports, that all appropriate measures are taken

to identify clearly any biological medicinal product prescribed, dispensed, or sold in

their territory that is the subject of a suspected adverse reaction report, with due regard

to the name of the medicinal product, and the batch number.

For the purposes of paragraph 1, points (a) and (e), the Member States may impose specific

obligations on doctors, pharmacists and other healthcare professionals.

Article 98

Member State delegation of pharmacovigilance tasks

A Member State may delegate any of the tasks entrusted to it under this Chapter to another

Member State subject to a written agreement of the latter. Each Member State may represent

no more than one other Member State.

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The delegating Member State shall inform the Commission, the Agency and all other Member

States of the delegation in writing. The delegating Member State and the Agency shall make

that information publicly available.

Article 99

Marketing authorisation holder pharmacovigilance system

Marketing authorisation holders shall operate a pharmacovigilance system for the fulfilment

of their pharmacovigilance tasks equivalent to the relevant Member State’s

pharmacovigilance system referred to in Article 96(1).

Marketing authorisation holders shall by means of the pharmacovigilance system referred to

in Article 96(1) evaluate all information scientifically, consider options for risk minimisation

and prevention and take appropriate measures as necessary.

Marketing authorisation holders shall perform a regular audit of their pharmacovigilance

system. They shall place a note concerning the main findings of the audit on the

pharmacovigilance system master file and, based on the audit findings, ensure that an

appropriate corrective action plan is prepared and implemented. Once the corrective actions

have been fully implemented, the note may be removed.

As part of the pharmacovigilance system, marketing authorisation holders shall:

(a) have permanently and continuously at their disposal an appropriately qualified person

responsible for pharmacovigilance;

(b) maintain and make available on request by a competent authority a pharmacovigilance

system master file;

(d) monitor the outcome of risk minimisation measures that are contained in the risk

management plan pursuant to Article 21 or that are laid down as conditions of the

marketing authorisation pursuant to Articles 44 (1) points (a)-(g) and point (i), 45 and

any obligations imposed in accordance with Article 87 (1) points (a) and (b);

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(e) update the risk management system and monitor pharmacovigilance data to determine

whether there are new risks or whether risks have changed or whether there are changes

to the benefit-risk balance of medicinal products.

The qualified person referred to in paragraph 4, point (a), shall reside and operate in the

Union and shall be responsible for the establishment and maintenance of the

pharmacovigilance system. The marketing authorisation holder shall submit the name and

contact details of the qualified person to the competent authority of the Member State and the

Agency.

The marketing authorisation holder shall, on request from the competent authority of a

Member State, nominate a contact person for pharmacovigilance issues in that Member State

who shall report to the qualified person referred to in paragraph 4, point (a).

To ensure patient’s safety the marketing authorisation holder shall have procedures in

place to ensure continued compliance with their pharmacovigilance tasks for an

appropriate period after a marketing authorisation has been withdrawn or revoked.

Article 100

Risk management system

Without prejudice to paragraph 2, 3 and 4, Hholders of marketing authorisations granted

before 21 July 2012 shall, by way of derogation from Article 99(4), point (c), not be required

to operate a risk management system for each of these medicinal products.

The competent authority of a Member State may impose an obligation on a marketing

authorisation holder of a national marketing authorisation to operate a risk management

system, as referred to in Article 99(4), point (c), if there are concerns about the risks affecting

the benefit-risk balance of an authorised medicinal product. In that context, the competent

authority of a Member State shall also oblige the marketing authorisation holder to submit a

risk management plan for the risk management system that they intend to introduce for the

medicinal product concerned.

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The obligation referred to in paragraph 2 shall be duly justified, notified in writing, and shall

include the timeframe for submission of the risk management plan.

The competent authority of a Member State shall provide the marketing authorisation holder

with an opportunity to submit written observations in response to the imposition of the

obligation within a time limit which it shall specify, if the marketing authorisation holder so

requests within 30 days of receipt of the written notification of the obligation.

On the basis of the written observations submitted by the marketing authorisation holder, the

competent authority of a Member State shall withdraw or confirm the obligation. Where the

competent authority of a Member State confirms the obligation, the marketing authorisation

shall be varied accordingly to include this and the measures to be taken as part of the risk

management system as conditions of the marketing authorisation referred to in Article 44 (1),

point (a).

Article 101

Funds for pharmacovigilance activities

The management of funds intended for activities connected with pharmacovigilance, the

operation of communication networks and market surveillance shall be under the permanent

control of the competent authorities of the Member States in order to guarantee their

independence in the performance of those pharmacovigilance activities.

Paragraph 1 shall not preclude the competent authorities of the Member States from charging

fees to marketing authorisation holders for performing pharmacovigilance activities on the

condition that the independence in the performance of those pharmacovigilance activities is

strictly guaranteed.

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Section 2

Transparency and communications

Article 102

National medicines web-portal

Each Member State shall set up and maintain a national medicines web-portal which shall be

linked to the European medicines web-portal established in accordance with Article 104 of

[revised Regulation (EC) No 726/2004]. By means of the national medicines web-portals, the

Member States shall make publicly available at least the following:

(a) public assessment reports, together with a summary thereof;

(b) summaries of product characteristics and package leaflets;

marketing authorisation in accordance with Chapter III;

(d) information on the different ways of reporting suspected adverse reactions to medicinal

products to competent authorities of the Member States by healthcare professionals and

patients, including the web-based structured forms referred to in Article 102 of [revised

Regulation (EC) No 726/2004].;

(e) information on prescription status of medicinal products authorised in their

territory.

The summaries referred to in paragraph 21, point (c), shall include, where relevant, a

description of additional risk minimisation measures.

Article 103

Publication of assessment

The Agency shall make publicly available the final assessment conclusions, recommendations,

opinions and decisions referred to in Articles 107 to 116, by means of the European medicines web-

portal.

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Article 104

Public announcements

As soon as the marketing authorisation holder intends to make a public announcement relating

to information on pharmacovigilance concerns in relation to the use of a medicinal product,

and in any event at the same time or before the public announcement is made, they shall be

required to inform the competent authorities of the Member States, the Agency and the

Commission.

The marketing authorisation holder shall ensure that information to the public is presented

objectively and is not misleading.

Unless urgent public announcements are required for the protection of public health, the

Member States, the Agency and the Commission shall inform each other not less than 24

hours prior to a public announcement relating to information on pharmacovigilance concerns.

For active substances contained in medicinal products authorised in more than one Member

State, the Agency shall be responsible for the coordination between competent authorities of

the Member States of safety announcements and shall provide timetables for the information

being made publicly available.

Under the coordination of the Agency, the Member States shall make all reasonable efforts to

agree on a common message in relation to the safety of the medicinal product concerned and

the timetables for their distribution. The Pharmacovigilance Risk Assessment Committee

shall, at the request of the Agency, provide advice on those safety announcements.

When the Agency or competent authorities of the Member States make publicly available

information referred to in paragraphs 2 and 3, any personal data or data of a commercially

confidential nature shall be deleted unless its public disclosure is necessary for the protection

of public health.

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Section 3

Recording and reporting of suspected adverse reactions

Article 105

Recording and reporting of suspected adverse reactions by the marketing authorisation holder

Marketing authorisation holders shall record all suspected adverse reactions in the Union or in

third countries that are brought to their attention, whether reported spontaneously by patients

or healthcare professionals, or occurring in the context of a post-authorisation study including

data relating to suspected adverse reactions off-label occuring where the use of the product

is used outside the terms of the marketing authorisation.

Marketing authorisation holders shall ensure that those reports are accessible at a single point

within the Union.

By way of derogation from the first subparagraph, suspected adverse reactions occurring in

the context of a clinical trial shall be recorded and reported in accordance with Regulation

(EU) No 536/2014.

Marketing authorisation holders shall not refuse to consider reports of suspected adverse

reactions received electronically or by any other appropriate means from patients or

healthcare professionals, including reports received in accordance with Article 105a.

Marketing authorisation holders shall submit electronically to the database and data-

processing network referred to in Article 101 of [revised Regulation (EC) No 726/2004]

(‘Eudravigilance database’) information on all serious suspected adverse reactions that occur

in the Union and in third countries within 15 days following the day on which the marketing

authorisation holder concerned gained knowledge of the event.

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Marketing authorisation holders shall submit electronically to the Eudravigilance database

information on all non-serious suspected adverse reactions that occur in the Union, within 90

days following the day on which the marketing authorisation holder concerned gained

knowledge of the event.

For medicinal products containing active substances referred to in the list of publications

monitored by the Agency pursuant to Article 105 of [revised Regulation (EC) No 726/2004],

marketing authorisation holders shall not be required to report to the Eudravigilance database

the suspected adverse reactions recorded in the listed publications, but they shall monitor all

other medical literature and report any suspected adverse reactions recorded therein.

Marketing authorisation holders shall establish procedures in order to obtain accurate and

verifiable data for the scientific evaluation of suspected adverse reaction reports. They shall

also collect follow-up information on those reports and submit the updates to the

Eudravigilance database. Reports obtained from the ‘Eudravigilance database’ shall not

be re-submitted by the marketing authorisation holders to the ‘Eudravigilance

database’, unless they contain additional information provided by the reporter.

Marketing authorisation holders shall collaborate with the Agency and the competent

authorities of the Member States in the detection of duplicates of suspected adverse reaction

reports.

This Article shall apply mutatis mutandis to undertakings supplying medicinal products used

in accordance with Article 3, paragraphs 1 or 2.

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Article 105a

Recording and reporting of suspected adverse reactions by wholesale distributors

Wholesale distributors that distribute medicinal products in accordance with Article 162(3) to

(5) shall record all suspected adverse reactions with regard to those medicinal products which

are brought to their attention, whether reported spontaneously by patients or by healthcare

professionals, including suspected adverse reactions occuring where the product is used

outside the terms of the marketing authorisation. They shall transmit those reports

immediately to the marketing authorisation holder holding the marketing authorisation in the

source Member State.

Article 106

Recording and reporting of suspected adverse reactions by Member States

Each Member State shall record all suspected adverse reactions that occur in its territory and

that which are brought to its attention from healthcare professionals and patients. This shall

include all authorised medicinal products and medicinal products used in accordance with

Article 3, paragraphs 1 or 2. Member States shall involve patients and healthcare

professionals, as appropriate, in the follow-up of any reports they receive in order to comply

with Article 97(1), points (c) and (e).

Member States shall ensure that reports of such reactions may be submitted by means of the

national medicines web-portals or by other means.

For reports submitted by a marketing authorisation holder, Member States on whose territory

the suspected adverse reaction occurred may involve the marketing authorisation holder in the

follow-up of the reports.

Member States shall collaborate with the Agency and the marketing authorisation holders in

the detection of duplicates of suspected adverse reaction reports.

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Member States shall, within 15 days following the receipt of the reports of serious suspected

adverse reactions referred to in paragraph 1, submit the reports electronically to the

Eudravigilance database.

Member States shall, within 90 days from the receipt of the reports referred to in paragraph 1,

submit reports of non-serious suspected adverse reactions electronically to the Eudravigilance

database.

Marketing authorisation holders and marketing authorisation applicants shall have access

to the reports referred to in this paragraph through the Eudravigilance database.

Member States shall ensure that reports of suspected adverse reactions arising from an error

associated with the use of a medicinal product that are brought to their attention are made

available to the Eudravigilance database and to any authorities, bodies, organisations or

institutions, responsible for patient safety within that Member State concerned. They shall

also ensure that the authorities responsible for medicinal products within that Member State

are informed of any suspected adverse reactions brought to the attention of any other authority

within that Member State. These reports shall be appropriately identified in the forms referred

to in Article 102 of [revised Regulation (EC) No 726/2004].

Unless there are justifiable grounds resulting from pharmacovigilance activities, Member

States shall not impose any additional obligations on marketing authorisation holders for the

reporting of suspected adverse reactions.

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Section 4

Periodic safety update reports

Article 107

Periodic safety update reports

Marketing authorisation holders shall submit to the Agency periodic safety update reports

containing:

(a) summaries of data relevant to the benefit-risk balance of the medicinal product,

including results of all studies with a consideration of their potential impact on the

marketing authorisation;

(b) a scientific evaluation of the benefit-risk balance of the medicinal product;

possession of the marketing authorisation holder relating to the volume of prescriptions,

including an estimate of the population exposed to the medicinal product.

The data provided in accordance with the first subparagraph, point (c), shall differentiate

between sales and volumes generated within the Union and those generated outside the

Union.

The evaluation referred to in paragraph 1, first subparagraph, point (b), shall be based on all

available data, including data from clinical trials in unauthorised therapeutic indications and

populations.

The periodic safety update reports shall be submitted electronically.

The Agency shall make available the reports referred to in paragraph 1 to the competent

authorities of the Member States, the members of the Pharmacovigilance Risk Assessment

Committee, the Committee for Medicinal Products for Human Use and the coordination group

by means of the repository referred to in Article 103 of [revised Regulation (EC) No

726/2004].

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By way of derogation from paragraph 1, the marketing authorisation holders for medicinal

products referred to in Articles 9, or 13, and the registration holders for medicinal products

referred to in Articles 126 or 134(1), shall only be required to submit periodic safety update

reports for such medicinal products to the competent authority in the following cases:

(a) where such obligation has been laid down as a condition in the marketing authorisation

in accordance with Articles 44 or 45; or

(b) when requested by a competent authority on the basis of concerns relating to

pharmacovigilance data or due to the lack of periodic safety update reports relating to an

active substance after the marketing authorisation has been granted.

By way of derogation from paragraph 1, the registration holders for medicinal products

referred to in Articles 126 or 134(1), shall only be required to submit periodic safety

update reports for such medicinal products when requested by a competent authority on

the basis of concerns relating to pharmacovigilance data.

The assessment reports of the periodic safety update reports referred to in the first

subparagraph shall be communicated by the competent authority to the Pharmacovigilance

Risk Assessment Committee, which shall consider whether there is a need for a single

assessment report for all marketing authorisations for medicinal products containing the same

active substance and which shall inform the coordination group or the Committee for

Medicinal Products for Human Use accordingly, in order to apply the procedures laid down in

Articles 108(4) and 110.

Article 108

Frequency of periodic safety update reports

The frequency with which the periodic safety update reports are to be submitted shall be

specified in the marketing authorisation.

The dates of submission according to the specified frequency shall be calculated from the date

when then marketing authorisation was granted.

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Holders of marketing authorisations which have been granted before 21 July 2012, and for

which the frequency and dates of submission of the periodic safety update reports are not laid

down as a condition to the marketing authorisation, shall submit the periodic safety update

reports in accordance with the second subparagraph until another frequency or other dates of

submission of the reports are laid down in the marketing authorisation or determined in

accordance with the paragraphs 4, 5 and 6.

Periodic safety update reports shall be submitted to the competent authorities immediately

upon request or in accordance with the following:

(a) where a medicinal product has not yet been placed on the market, at least every six

months following the marketing authorisation and until the placing on the market;

(b) where a medicinal product has been placed on the market, at least every six months

once a year during the first two five years following the initial placing on the market,

once a year for the following two years and ata three-yearly intervals for the

subsequent six years and with a five years interval thereafter.

Paragraph 2 shall also apply to medicinal products that are authorised only in one Member

State and for which paragraph 4 does not apply.

Where medicinal products that are subject to different marketing authorisations contain the

same active substance or the same combination of active substances, the frequency and dates

of submission of the periodic safety update reports resulting from the application of the

paragraphs 1 and 2 may be amended and harmonised to enable a single assessment to be made

in the context of a periodic safety update report work-sharing procedure and to set a Union

reference date from which the submission dates to be calculated.

The harmonised frequency for the submission of the reports and the Union reference date may

be determined, after consultation of the Pharmacovigilance Risk Assessment Committee, by

one of the following:

(a) the Committee for Medicinal Products for Human Use, where at least one of the

marketing authorisations for the medicinal products containing the active substance

concerned has been granted in accordance with the centralised procedure provided for in

Article 3 of [revised Regulation (EC) No 726/2004];

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(b) the coordination group, in other cases than those referred to in point (a).

The harmonised frequency for the submission of the reports determined pursuant to the first

and second subparagraphs shall be made publicly available by the Agency. Marketing

authorisation holders shall submit an application for a variation of the marketing authorisation

accordingly.

For the purposes of paragraph 4, the Union reference date for medicinal products containing

the same active substance or the same combination of active substances shall be one of the

following:

(a) the date when the first marketing authorisation was granted in the Union for a medicinal

product containing that active substance or that combination of active substances;

(b) if the date referred to in point (a) cannot be ascertained, the earliest of the known dates

of the marketing authorisations for a medicinal product containing that active substance

or that combination of active substances.

Marketing authorisation holders shall be allowed to submit requests to the Committee for

Medicinal Products for Human Use or the coordination group, as appropriate, to determine

Union reference dates or to change the frequency of submission of periodic safety update

reports on one of the following grounds:

(a) for reasons relating to public health;

(b) in order to avoid a duplication of the assessment;

Such requests shall be submitted in writing and shall be duly justified. The Committee for

Medicinal Products for Human Use or the coordination group shall, following the consultation

with the Pharmacovigilance Risk Assessment Committee, either approve or deny such

requests. Any change in the dates or the frequency of submission of periodic safety update

reports shall be made publicly available by the Agency. The marketing authorisation holders

shall submit an application for a variation of the marketing authorisation accordingly.

The Agency shall make public a list of Union reference dates and frequency of submission of

periodic safety update reports by means of the European medicines web-portal.

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Any change to the dates of submission and frequency of periodic safety update reports

specified in the marketing authorisation as a result of the application of the paragraphs 4, 5

and 6 shall take effect four months after the date of the publication referred to in the first

subparagraph.

Article 109

Assessment of periodic safety update reports

The competent authorities of the Member State shall assess periodic safety update reports to

determine whether there are new risks or whether risks have changed or whether there are changes

to the benefit-risk balance of medicinal products.

Article 110

Single assessment of periodic safety update reports

single assessment of periodic safety update reports shall be performed for medicinal

products authorised in more than one Member State and, in the cases referred to in Article

108, paragraphs 4, 5 and 6, for all medicinal products containing the same active substance or

the same combination of active substances and for which a Union reference date and a

frequency of periodic safety update reports has been established.

The single assessment shall be conducted by either of the following:

(a) a Member State appointed by the coordination group where none of the marketing

authorisations concerned has been granted in accordance with the centralised procedure

provided for in Article 3 of [revised Regulation (EC) No 726/2004];

(b) a rapporteur appointed by the Pharmacovigilance Risk Assessment Committee, where at

least one of the marketing authorisations concerned has been granted in accordance with

the centralised procedure provided for in Article 3 of [revised Regulation (EC) No

726/2004].

When selecting the Member State in accordance with the second subparagraph, point (a), the

coordination group shall take into account whether any Member State is acting as a reference

Member State, in accordance with Chapter III, Sections 3 and 4.

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The Member State or rapporteur, as appropriate, shall prepare an assessment report within 60

days of receipt of the periodic safety update report and send it to the Agency and to the

Member States concerned. The Agency shall send the report to the marketing authorisation

holder.

Within 30 days of receipt of the assessment report, the Member States and the marketing

authorisation holder may submit comments to the Agency and to the rapporteur or Member

State. Where the report includes questions to the marketing authorisation holder, the

holder shall provide answers within those 30 days.

Following the receipt of the comments referred to in paragraph 2, the rapporteur or Member

State shall within 15 days update the assessment report taking into account any comments

submitted, and forward it to the Pharmacovigilance Risk Assessment Committee. The

Pharmacovigilance Risk Assessment Committee shall adopt the assessment report with or

without further changes at its next meeting and issue a recommendation. The recommendation

shall mention any divergent positions with the grounds on which they are based. The Agency

shall include the adopted assessment report and the recommendation in the repository set up

under Article 103 of [revised Regulation (EC) No 726/2004] and forward them to the

marketing authorisation holder.

Article 111

Regulatory action on periodic safety update reports

Following the assessment of periodic safety update reports referred to in Article 107 109, the

competent authorities of the Member States shall consider whether any action concerning the

marketing authorisation for the medicinal product concerned is necessary and shall maintain, vary,

suspend or revoke the marketing authorisation as appropriate.

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Article 112

Procedure for regulatory action on periodic safety update reports

In the case of a single assessment of periodic safety update reports in accordance with Article

110(1) which recommends action concerning more than one marketing authorisation that does

not include any centralised marketing authorisation, the coordination group shall, within 30

days of receipt of the assessment report of the Pharmacovigilance Risk Assessment

Committee, consider the assessment report and reach a position on the maintenance, variation,

suspension or revocation of the marketing authorisations concerned, including a timetable for

the implementation of the agreed position.

If, within the coordination group, the Member States represented reach an agreement on the

action to be taken by consensus, the chairperson shall record the agreement and send it to the

marketing authorisation holder and the Member States. The Member States shall adopt

necessary measures to maintain, vary, suspend or revoke the marketing authorisations

concerned in accordance with the timetable for implementation determined in the agreement.

In the event of a variation, the marketing authorisation holder shall submit to the competent

authorities of the Member States an appropriate application for a modification, including an

updated summary of product characteristics and an updated package leaflet within the

determined timetable for implementation.

If an agreement by consensus cannot be reached, the position of the majority of the Member

States represented within the coordination group shall be forwarded to the Commission which

shall apply the procedure laid down in Article 42.

Where the agreement reached by the Member States represented within the coordination

group or the position of the majority of Member States differs from the recommendation of

the Pharmacovigilance Risk Assessment Committee, the coordination group shall attach to the

agreement or the majority position a detailed explanation of the scientific grounds for the

differences together with the recommendation.

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In the case of a single assessment of periodic safety update reports in accordance with Article

110(1) that recommends action concerning more than one marketing authorisation that

includes at least one centralised marketing authorisation, the Committee for Medicinal

Products for Human Use shall, within 30 days of receipt of the report of the

Pharmacovigilance Risk Assessment Committee, consider the report and adopt an opinion on

the maintenance, variation, suspension or revocation of the marketing authorisations

concerned, including a timetable for the implementation of the opinion.

Where the opinion of the Committee for Medicinal Products for Human Use referred to in

paragraph 3 differs from the recommendation of the Pharmacovigilance Risk Assessment

Committee, the Committee for Medicinal Products for Human Use shall attach to its opinion a

detailed explanation of the scientific grounds for the differences together with the

recommendation.

On the basis of the opinion of the Committee for Medicinal Products for Human Use referred

to in paragraph 3, the Commission shall, by means of implementing acts:

(a) adopt a decision addressed to the Member States concerning the measures to be taken in

respect of marketing authorisations granted by the Member States and concerned by the

procedure provided for in this section; and

(b) where the opinion states that regulatory action concerning the marketing authorisation is

necessary, adopt a decision to vary, suspend or revoke the centralised marketing

authorisations and concerned by the procedure provided for in this section.

Article 42 shall apply to the adoption of the decision referred to in paragraph 5, point (a), and

to its implementation by the Member States.

Article 13 of [revised Regulation (EC) No 726/2004] shall apply to the decision referred to in

paragraph 5, point (b). Where the Commission adopts such decision, it may also adopt a

decision addressed to the Member States pursuant to Article 55 57 of [revised Regulation

(EC) No 726/2004].

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Section 5

Signal detection

Article 113

Signal monitoring and detection

Regarding medicinal products authorised in accordance with Chapter III, competent

authorities of the Member States shall in collaboration with the Agency, take the following

measures:

(a) monitor the outcome of risk minimisation measures contained in risk management plans

and of the conditions referred to in Articles 44 (1) points (a)-(g) and point (i), 45 and

any obligations imposed in accordance with Article 87 (1) points (a), (b) and (ba);

(b) assess updates to the risk management system;

risks or whether risks have changed and whether those risks impact on the benefit-risk

balance.

The Pharmacovigilance Risk Assessment Committee shall perform the initial analysis and

prioritisation of signals of new risks or risks that have changed or changes to the benefit-risk

balance. Where it considers that follow-up action may be necessary, the assessment of those

signals and agreement on any subsequent action concerning the marketing authorisation shall

be conducted in a timescale commensurate with the extent and seriousness of the issue.

Where appropriate, the assessment of those signals may be included in a pending

assessment of a periodic safety update report or a pending procedure in accordance with

Articles 92 to 95 and 114-116 of this Directive or Article 55 of [revised Regulation].

The Agency and competent authorities of the Member States and the marketing authorisation

holder shall inform each other in the event of new risks or risks that have changed or changes

to the benefit-risk balance being detected.

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Member States shall ensure that marketing authorisation holders inform the Agency and

competent authorities of the Member State in the event of new risks or risks that have

changed or when changes to the benefit-risk balance have been detected.

Section 6

Urgent Union procedure

Article 114

Initiation of an urgent Union procedure

A Member State or the Commission, as appropriate, shall, on the basis of concerns resulting

from the evaluation of data from pharmacovigilance activities, initiate the procedure provided

for in this Section (the ‘urgent Union procedure’) by informing the other Member States, the

Agency and the Commission where:

(a) it considers suspending or revoking a marketing authorisation;

(b) it considers prohibiting the supply of a medicinal product;

(d) it is informed by the marketing authorisation holder that, on the basis of safety concerns,

the marketing authorisation holder has interrupted the placing on the market of a

medicinal product or has taken action to have a marketing authorisation withdrawn, or

intends to take such action or has not applied for the renewal of a marketing

authorisation.

A Member State or the Commission, as appropriate, shall, on the basis of concerns resulting

from the evaluation of data from pharmacovigilance activities, inform the other Member

States, the Agency and the Commission where it considers that a new contraindication, a

reduction in the recommended dose or a restriction to the therapeutic indications of a

medicinal product is necessary. The information shall outline the action considered and the

reasons therefore.

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Any Member State or the Commission, as appropriate, shall, when urgent action is considered

necessary in any of the cases referred to in the first subparagraph, initiate the urgent Union

procedure.

Where the urgent Union procedure is not initiated, for medicinal products authorised in

accordance with Chapter III, Sections 3 and 4, the case shall be brought to the attention of the

coordination group.

Article 95 shall apply where the interests of the Union are involved.

Where the urgent Union procedure is initiated, the Agency shall verify whether the safety

concern relates to medicinal products other than the one covered by the information, or

whether the safety concern is common to all medicinal products belonging to the same range

or therapeutic class.

Where the medicinal product involved is authorised in more than one Member State, the

Agency shall without undue delay inform the initiator of the urgent Union procedure of the

outcome of the verification, and the procedures laid down in Articles 115 and 116 shall apply.

Otherwise, the safety concern shall be addressed by the Member State concerned. The Agency

or the Member State, as applicable, shall make the information that the urgent Union

procedure has been initiated available to marketing authorisation holders.

Without prejudice to paragraphs 1 and 2, and Articles 115 and 116, a Member State may,

where urgent action is necessary to protect public health, suspend the marketing authorisation

and prohibit the use of the medicinal product concerned on its territory until a definitive

decision is adopted in the urgent Union procedure. It shall inform the Commission, the

Agency and the other Member States no later than the following working day of the reasons

for its action.

At any stage of the procedure laid down in Articles 115 and 116, the Commission may request

a Member State in which the medicinal product is authorised to take temporary measures

immediately.

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Where the scope of the procedure, as determined in accordance with paragraphs 1 and 2,

includes medicinal products covered by centralised marketing authorisations, the Commission

may, at any stage of the urgent Union procedure, take temporary measures immediately in

relation to those marketing authorisations.

The information referred to in this Article may relate to individual medicinal products or to a

range of medicinal products or a therapeutic class.

If the Agency identifies that the safety concern relates to more medicinal products than those

that are covered by the information or that the safety concern is common to all medicinal

products belonging to the same range or therapeutic class, it shall extend the scope of the

procedure accordingly.

Where the scope of the urgent Union procedure concerns a range of medicinal products or

therapeutic class, medicinal products covered by the centralised marketing authorisation, that

belong to that range or class shall also be included in the procedure.

At the time the information referred to in paragraphs 1 and 2 is provided, the Member State

shall make available to the Agency all relevant scientific information that it has at its disposal

and any assessment by the Member State.

Article 115

Urgent Union procedure scientific assessment

Following receipt of the information referred to in Article 114, paragraphs 1 and 2, the

Agency shall publicly announce the initiation of the urgent Union procedure by means of the

European medicines web-portal. In parallel, Member States may publicly announce the

initiation of the procedure on their national medicines web-portals.

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The announcement shall specify the matter submitted to the Agency in accordance with

Article 114, and the medicinal products and, where applicable, the active substances

concerned. It shall contain information on the right of the marketing authorisation holders,

healthcare professionals and the public to submit to the Agency information relevant to the

procedure and it shall state how such information may be submitted.

The Pharmacovigilance Risk Assessment Committee shall assess the matter that has been

submitted to the Agency in accordance with Article 114. The rapporteur, as referred to in

Article 152 of [revised Regulation (EC) No 726/2004], shall closely collaborate with the

rapporteur appointed by the Committee for Medicinal Products for Human Use and with the

reference Member State for the medicinal products concerned.

For the purposes of the assessment referred to in the first subparagraph, the marketing

authorisation holder may submit comments in writing.

Where the urgency of the matter permits, the Pharmacovigilance Risk Assessment Committee

may hold public hearings, where it considers that this is appropriate on justified grounds

particularly with regard to the extent and seriousness of the safety concern. The hearings shall

be held in accordance with the modalities specified by the Agency and shall be announced by

means of the European medicines web-portal. In the hearing due regard shall be given to

the therapeutic effect of the medicinal product. The announcement shall specify the

modalities of participation.

The Agency shall, in consultation with the parties concerned, draw up Rules of Procedure on

the organisation and conduct of public hearings, in accordance with Article 163 of [revised

Regulation (EC) No 726/2004].

Where a marketing authorisation holder or another person intending to submit information,

has confidential data relevant to the subject matter of the procedure, they may request

permission to present that data to the Pharmacovigilance Risk Assessment Committee in a

non-public hearing.

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Within 60 days of the submission of the information, the Pharmacovigilance Risk Assessment

Committee shall make a recommendation, stating the reasons on which it is based, having due

regard to the therapeutic effect of the medicinal product. The recommendation shall mention

any divergent positions and the grounds on which they are based. In the case of urgency, and

on the basis of a proposal by its chairperson, the Pharmacovigilance Risk Assessment

Committee may agree to a shorter deadline. The recommendation shall include any or a

combination of the following conclusions:

(a) no further evaluation or action is required at Union level;

(b) the marketing authorisation holder should conduct further evaluation of data and carry

out a follow-up of the results of that evaluation;

carry out a follow up evaluation of the results of that study;

(d) the Member States or marketing authorisation holder should implement risk

minimisation measures;

(e) the marketing authorisation should be suspended, revoked or not renewed;

(f)

the marketing authorisation should be varied.

For the purposes of paragraph 3, point (d), the recommendation shall specify the risk

minimisation measures recommended and any conditions or restrictions to which the

marketing authorisation should be made subject, including the timeline for implementation.

For the purposes of paragraph 3, point (f), where it is recommended to change or add

information in the summary of product characteristics or the labelling or package leaflet, the

recommendation shall suggest the wording of such changed or added information and shall

indicate where in the summary of product characteristics, the labelling or package leaflet such

wording should be placed.

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Article 116

Follow-up of recommendation made in the framework of the urgent Union procedure

Where the scope of the urgent Union procedure, as determined in accordance with Article

114(6), does not include any centralised marketing authorisation, the coordination group shall,

within 30 days of receipt of the recommendation of the Pharmacovigilance Risk Assessment

Committee, consider the recommendation and reach a position on the maintenance, variation,

suspension, revocation or refusal of the renewal of the marketing authorisation concerned,

including a timetable for the implementation of the agreed position. Where an urgent adoption

of the position is necessary, the coordination group may, on the basis of a proposal by its

chairperson, agree to a shorter deadline.

If, within the coordination group, the Member States represented reach an agreement on the

action to be taken by consensus, the chairperson shall record the agreement and send it to the

marketing authorisation holder and the Member States. The Member States shall adopt

necessary measures to maintain, vary, suspend, revoke or refuse renewal of the marketing

authorisation concerned in accordance with the implementation timetable determined in the

agreement.

In the event that a variation is agreed upon, the marketing authorisation holder shall submit to

the competent authorities of the Member States an appropriate application for a variation,

including an updated summary of product characteristics and an updated package leaflet

within the determined timetable for implementation.

If an agreement by consensus cannot be reached, the position of the majority of the Member

States represented within the coordination group shall be forwarded to the Commission which

shall apply the procedure laid down in Article 42.

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Where the agreement reached by the Member States represented within the coordination

group or the position of the majority of the Member States represented within the

coordination group differs from the recommendation of the Pharmacovigilance Risk

Assessment Committee, the coordination group shall attach to the agreement or majority

position a detailed explanation of the scientific grounds for the differences together with the

recommendation.

Where the scope of the procedure, as determined in accordance with Article 114(6), includes

at least one centralised marketing authorisation, the Committee for Medicinal Products for

Human Use shall, within 30 days of receipt of the recommendation of the Pharmacovigilance

Risk Assessment Committee, consider the recommendation and adopt an opinion on the

maintenance, variation, suspension, revocation or refusal of the renewal of the marketing

authorisations concerned. Where an urgent adoption of the opinion is necessary, the

Committee for Medicinal Products for Human Use may, on the basis of a proposal by its

chairperson, agree to a shorter deadline.

Where the opinion of the Committee for Medicinal Products for Human Use differs from the

recommendation of the Pharmacovigilance Risk Assessment Committee, the Committee for

Medicinal Products for Human Use shall attach to its opinion a detailed explanation of the

scientific grounds for the differences together with the recommendation.

On the basis of the opinion of the Committee for Medicinal Products for Human Use referred

to in paragraph 3, the Commission shall, by means of implementing acts:

(a) adopt a decision addressed to the Member States concerning the measures to be taken in

respect of marketing authorisations that are granted by the Member States and that are

subject to the urgent Union procedure;

(b) where the opinion states that regulatory action concerning the marketing authorisation is

necessary, adopt a decision to vary, suspend, revoke or refuse the renewal of the

centralised marketing authorisations and concerned by the procedure provided for in

this section.

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Article 42 shall apply to the adoption of the decision referred to in paragraph 4, point (a), and

to its implementation by the Member States.

Article 13 of [revised Regulation (EC) No 726/2004] shall apply to the decision referred to in

paragraph 4, point (b). Where the Commission adopts such decision, it may also adopt a

decision addressed to the Member States pursuant to Article 55 57 of [revised Regulation

(EC) No 726/2004].

Section 7

Supervision of post-authorisation safety studies

Article 117

Non-interventional post-authorisation safety studies

This Section applies to non-interventional post-authorisation safety studies that are initiated,

managed or financed by the marketing authorisation holder voluntarily or pursuant to

obligations imposed in accordance with Articles 44 or 87, and that involve the collection of

safety data from patients or healthcare professionals.

This Section is without prejudice to Member States and Union requirements for ensuring the

well-being and rights of participants in non-interventional post-authorisation safety studies.

The studies shall not be performed where the act of conducting the study promotes the use of

a medicinal product.

Payments to healthcare professionals for participating in non-interventional post-authorisation

safety studies shall be restricted to the compensation for time and expenses incurred.

The competent authority of the Member State may require the marketing authorisation holder

to submit the protocol and the progress reports to the competent authorities of the Member

States in which the study is conducted.

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The marketing authorisation holder shall send the final report of the study to the competent

authorities of the Member States in which the study was conducted within 12 months of the

end of data collection.

While a study is being conducted, the marketing authorisation holder shall monitor the data

generated and consider its implications for the benefit-risk balance of the medicinal product

concerned.

Any new information that might influence the evaluation of the benefit-risk balance of the

medicinal product shall be communicated to the competent authorities of the Member State in

which the medicinal product has been authorised in accordance with Article 90.

The obligation laid down in the second subparagraph is without prejudice to the information

on the results of studies that the marketing authorisation holder shall make available by means

of the periodic safety update reports as laid down in Article 107.

Articles 118 to 121 shall apply exclusively to studies referred to in paragraph 1 that are

conducted pursuant to an obligation imposed in accordance with Articles 44 or 87.

Article 118

Agreement of a protocol for a non-interventional post-authorisation safety study

Before a study is conducted, the marketing authorisation holder shall submit a draft protocol

to the Pharmacovigilance Risk Assessment Committee, except for studies to be conducted in

only one Member State that requests the study in accordance with Article 87. For such

studies, the marketing authorisation holder shall submit a draft protocol to the competent

authority of the Member State in which the study is conducted.

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Within 60 days of the submission of the draft protocol referred to in paragraph 1 the

competent authority of the Member State or the Pharmacovigilance Risk Assessment

Committee, as appropriate, shall issue:

(a) a letter endorsing the draft protocol;

(b) a letter of objection, which shall set out in detail the grounds for the objection, where:

(i)

it considers that the conduct of the study promotes the use of a medicinal product;

(ii) it considers that the design of the study does not fulfil the study objectives; or

falling under the scope of Regulation (EU) No 536/2014.

The study may commence only when the written endorsement from the competent authority

of the Member State or the Pharmacovigilance Risk Assessment Committee, as appropriate,

has been issued.

Where a letter of endorsement of the draft protocol as referred to in paragraph 2, point (a), has

been issued, the marketing authorisation holder shall forward the protocol to the competent

authorities of the Member States in which the study is to be conducted and may thereafter

commence the study according to the endorsed protocol.

Article 119

Update of a protocol for a non-interventional post-authorisation safety study

After a study has been commenced, any substantial amendments to the protocol shall be submitted,

before their implementation, to the competent authority of the Member State or to the

Pharmacovigilance Risk Assessment Committee, as appropriate. The competent authority of the

Member State or the Pharmacovigilance Risk Assessment Committee, as appropriate, shall assess

the amendments and inform the marketing authorisation holder of its endorsement or objection.

Where applicable, the marketing authorisation holder shall inform the Member States in which the

study is conducted.

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Article 120

Final study report on a non-interventional post-authorisation safety study

Upon completion of the study, a final study report shall be submitted to the competent

authority of the Member State or the Pharmacovigilance Risk Assessment Committee within

12 months of the end of data collection unless a written waiver has been granted by the

competent authority of the Member State or the Pharmacovigilance Risk Assessment

Committee, as appropriate.

The marketing authorisation holder shall evaluate whether the results of the study have an

impact on the marketing authorisation and shall, if necessary, submit to the competent

authorities of the Member States an application to vary the marketing authorisation.

Together with the final study report, the marketing authorisation holder shall electronically

submit an abstract of the study results to the competent authority of the Member State or the

Pharmacovigilance Risk Assessment Committee.

Article 121

Recommendations following the submission of a final study report on non-interventional post-

authorisation safety studies

Based on the results of the study and after consultation of the marketing authorisation holder,

the Pharmacovigilance Risk Assessment Committee may make recommendations concerning

the marketing authorisation, stating the reasons on which they are based. The

recommendations shall mention any divergent positions and the grounds on which they are

based.

When recommendations for the variation, suspension or revocation of a national marketing

authorisation are made, the Member States represented within the coordination group shall

agree on a position on the matter taking into account the recommendation referred to in

paragraph 1 and shall include a timetable for the implementation of the agreed position.

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If, within the coordination group, the Member States represented reach an agreement on the

action to be taken by consensus, the chairperson shall record the agreement and send it to the

marketing authorisation holder and the Member States. The Member States shall adopt

necessary measures to vary, suspend or revoke the marketing authorisation concerned in

accordance with the implementation timetable determined in the agreement.

In the event that a variation is agreed upon, the marketing authorisation holder shall submit to

the competent authorities of the Member State an appropriate application for a variation,

including an updated summary of product characteristics and an updated package leaflet

within the determined timetable for implementation.

The agreement shall be made publicly available on the European medicines web-portal

established in accordance with Article 104 of [revised Regulation (EC) No 726/2004].

If an agreement by consensus cannot be reached, the position of the majority of the Member

States represented within the coordination group, with a detailed description of the matters

on which the other Member States have been unable to reach an agreement and of all

the divergent positions of Member States presented shall be forwarded to the Commission,

which shall apply the procedure laid down in Article 42.

Where the agreement reached by the Member States represented within the coordination

group or the position of the majority of Member States differs from the recommendation of

the Pharmacovigilance Risk Assessment Committee, the coordination group shall attach to the

agreement or majority position a detailed explanation of the scientific grounds for the

differences together with the recommendation.

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Section 8

Implementation, guidance and reporting

Article 122

Implementing measures related to pharmacovigilance activities

In order to harmonise the performance of the pharmacovigilance activities provided for in this

Directive, the Commission shall adopt implementing measures in the following areas for

which pharmacovigilance activities are provided for in Annex I, Articles 96, 99, 100, 105 to

107, 113, 118 and 120 by setting out:

(a) the content and the rules on the maintenance of the pharmacovigilance system master

file kept by the marketing authorisation holder;

(b) minimum requirements for the quality system for the performance of pharmacovigilance

activities by the competent authorities of the Member States and the marketing

authorisation holder;

performance of pharmacovigilance activities;

(d) minimum requirements for the monitoring of data in the Eudravigilance database to

determine whether there are new risks or whether risks have changed;

(e) the format and content of the electronic transmission of suspected adverse reactions by

Member States and the marketing authorisation holder;

(f)

the format and content of electronic periodic safety update reports and risk management

plans;

(g) the format of protocols, abstracts and final study reports for the post-authorisation safety

studies.

Those measures shall take account of the work on international harmonisation carried out in

the area of pharmacovigilance. and shall, where necessary, be revised to take account of

technical and scientific progress. Those measures shall be adopted in accordance with the

regulatory procedure referred to in Article 214(2).

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Article 123

Guidance to facilitate the performance of pharmacovigilance activities

The Agency shall, in cooperation with competent authorities of the Member States and other

interested parties, draw up:

(a) guidance on good pharmacovigilance practices for both competent authorities and marketing

authorisation holders;

(b) scientific guidance on post-authorisation efficacy studies.

Article 124

Reporting on pharmacovigilance tasks

The Agency shall make public a report on the performance of pharmacovigilance tasks by the

Member States and the Agency every three years. The first report shall be made public by [three

years after application date of [revised Regulation (EC) No 726/2004].

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Chapter X

Homeopathic medicinal products and traditional herbal medicinal

products

Section 1

Specific provisions applicable to homeopathic medicinal products

Article 125

Registration or authorisation of homeopathic medicinal products

Member States shall ensure that homeopathic medicinal products manufactured and placed on

the market in the Union are registered in accordance with Articles 126 and 127 or authorised

in accordance with Article 133(1), except where such homeopathic medicinal products are

covered by a registration or authorisation granted in accordance with national legislation on or

before 31 December 1993. In case of registrations, Chapter III, Sections 3 and 4, and Article

38, paragraphs 1, 2 and 3 shall apply mutatis mutandis.

Member States shall establish a simplified registration procedure referred to in Article 126 for

the homeopathic medicinal products.

Article 126

Simplified registration procedure for homeopathic medicinal products

Homeopathic medicinal products that satisfy all of the following conditions may be subject to

a simplified registration procedure:

(a) they are administered orally or externally;

(b) no specific therapeutic indication appears on the labelling of the medicinal product, is

conveyed in the name of the medicinal products, or in any information relating

thereto;

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1a. For the purposes of paragraph 1, point (c), the medicinal product may not contain either

more than one part per 10000 of the mother tincture or more than 1/100th of the smallest dose

used in allopathy with regard to active substances whose presence in an allopathic medicinal

product results in the obligation to submit a doctor’s prescription.

1b. The Commission is empowered to adopt delegated acts in accordance with Article 215 to

amend the first subparagph, point (c) paragraph 1a, in order to take account of scientific

progress.

At the time of registration, Member States shall determine the prescription status for the

dispensing of the homeopathic medicinal product..

The criteria and rules of procedure provided for in Article 1(10), point (ac), Article 30,

Chapter III, Section 6, 191, 195 and 204 shall apply by analogy mutatis mutandis to the

simplified registration procedure for homeopathic medicinal products, with the exception of

the proof of therapeutic efficacy.

Article 127

Application requirements for simplified registration

The holder of homeopathic medicinal product simplified registration shall be established

in the Union.

An application for a simplified registration may cover a series of homeopathic medicinal

products derived from the same homeopathic stock or stocks. The following shall be included

with the application in order to demonstrate, in particular, the pharmaceutical quality and the

batch-to-batch homogeneity of the homeopathic medicinal products concerned:

(a) the scientific name or other name given in a pharmacopoeia of the homeopathic stock or

stocks, together with a statement of the various routes of administration, pharmaceutical

forms and degree of dilution to be registered;

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(b) a dossier describing how the homeopathic stock or stocks are obtained and controlled,

and justifying their homeopathic use, on the basis of an adequate bibliography;

method of dilution and potentisation;

(ca) if the homeopathic medicinal product contains biological substances,

documentation on the measures taken to ensure its absence of pathogens;

(d) the manufacturing authorisation for the homeopathic medicinal product concerned;

(e) the copies or references to identify of any registrations or authorisations obtained for

the same homeopathic medicinal product in other Member States;

(f)

one or more mock-ups of the outer packaging and the immediate packaging of the

homeopathic medicinal products to be registered;

(g) the data concerning the stability of the homeopathic medicinal product and shelf life of

the homeopathic medicinal product;.

(h) name or company name and registered office of the applicant and, if the applicant

is not identical with the manufacturer, the name or company name and registered

office of the manufacturer.

Article 128

Application of decentralised and mutual recognition procedures to homeopathic medicinal products

Article 38, paragraphs 4 and 56, Articles 39 to 42 and 95 shall not apply to the homeopathic

medicinal products referred to in Article 126.

Chapter III, Sections 3 to 5, shall not apply to the homeopathic medicinal products referred to

in Article 133(2).

Article 129

Labelling of homeopathic medicinal products

Homeopathic medicinal products, with the exception of those referred to in Article 126(1), shall be

labelled in accordance with the provisions of Chapter VI and shall be identified by a reference on

their labels, in clear and legible form, to their homeopathic nature.

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Article 130

Specific requirements for labelling of certain homeopathic medicinal products

The labelling and, where appropriate, the package insert leaflet for homeopathic medicinal

products referred to in Article 126(1) in addition to the clear mention of the words

‘homeopathic medicinal product’, shall bear the following, and no other, information:

(a) the scientific name of the stock or stocks followed by the degree of dilution, making use

of the symbols of the pharmacopoeia used in accordance with Article 4(62);

(b) name and address of the registration holder and, where appropriate, of the manufacturer;

(d) pharmaceutical form and the content by weight, volume or number of doses of the

product;

(e) expiry date, in clear terms (month, year);

(f)

contents of the sales presentation;

(g) special storage precautions, if any;

(h) a special warning if necessary for the medicinal product;

(i)

manufacturer's batch number;

(j)

registration number;

(k) ‘homeopathic medicinal product without approved therapeutic indications’;

(l)

a warning advising the user to consult a doctor if the symptoms persist;.

(m) for the package leaflet: the date on which the package leaflet was last revised;

(n) a the list of those excipients known to have a recognised action or effect and

included in the detailed guidance published pursuant to Article 77.

As regards the first subparagraph, point (a), if the homeopathic medicinal product is

composed of two or more stocks, the scientific names of the stocks on the labelling may be

supplemented by an invented name.

Notwithstanding paragraph 1, Member States may require the use of certain types of labelling

in order to show:

(a) the price of the homeopathic medicinal product;

(b) the reimbursement conditions for refunds by social security bodies.

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Article 131

Advertising of homeopathic medicinal products

Chapter XIII shall apply to homeopathic medicinal products.

By derogation from paragraph 1, Article 176(1) shall not apply to medicinal products referred

to in Article 126(1).

However, only the information specified in Article 130(1) may be used in the advertising of

such homeopathic medicinal products.

Article 132

Exchange of information on homeopathic medicinal products

Member States shall communicate to each other all the information necessary to guarantee the

quality and safety of homeopathic medicinal products manufactured and marketed within the

Union, and in particular the information referred to in Articles 202 and 203.

Article 133

Other requirements for homeopathic medicinal products

Homeopathic medicinal products other than those referred to in Article 126(1) shall be

granted a marketing authorisation in accordance with Articles 6 and 9 to 14 and labelled in

accordance with Chapter VI.

A Member State may introduce or retain in its territory specific rules for the non-clinical tests

and clinical studies of homeopathic medicinal products other than those referred to in Article

126(1), in accordance with the principles and characteristics of homeopathy as practised in

that Member State.

In this case, the Member State concerned shall notify the Commission of the specific rules in

force.

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Chapter IX shall apply to homeopathic medicinal products, with the exception of those

referred to in Article 126(1). Chapter XI, Chapter XII, Section 1, and Chapter XIV shall apply

to homeopathic medicinal products.

Section 2

Specific provisions applicable to traditional herbal medicinal products

Article 134

Simplified registration procedure for traditional herbal medicinal products

Herbal medicinal products that satisfy all of the following conditions may be subject to a

simplified registration procedure (‘traditional-use registration’):

(a) they have therapeutic indications exclusively appropriate to traditional herbal medicinal

products that, by virtue of their composition and purpose, are intended and designed for

use without the supervision of a medical practitioner for diagnostic purposes or for

prescription or monitoring of treatment;

(b) they are exclusively for administration in accordance with a specified strength and

posology;

(d) the period of traditional use as laid down in Article 136(1), point (c), has elapsed;

(e) the data on the traditional use of the herbal medicinal product referred to in Article

136(1), point (c), are sufficient.

The data on the use of a medicinal product referred to in the first subparagraph, point (e), shall

be considered sufficient where the herbal medicinal product proves not to be harmful in the

specified conditions of use and the pharmacological effects or efficacy of the herbal medicinal

product are plausible on the basis of long-standing use and experience.

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Notwithstanding Article 4(1), point (64), the presence in the herbal medicinal product of

vitamins or minerals for the safety of which there is well-documented evidence shall not

prevent the herbal medicinal product from being eligible for registration in accordance with

paragraph 1, provided that the action of the vitamins or minerals is ancillary to that of the

herbal active substances regarding the specified claimed therapeutic indication(s).

However, in cases where the competent authorities judge that a herbal medicinal product that

fulfils the conditions laid down in paragraph 1 (‘traditional herbal medicinal product’) fulfils

the criteria for a national marketing authorisation in accordance with Article 5 or for a

simplified registration in accordance with Article 126, the provisions of this Section shall not

apply.

Article 135

Submission of dossier for traditional herbal medicinal product

The applicant and the holder of the traditional herbal medicinal product simplified

registration traditional-use registration holder shall be established in the Union.

In order to obtain a traditional-use registration, the applicant shall submit an application to the

competent authority of the Member State concerned.

Article 136

Application requirements for traditional-use registration

An application for traditional-use registration shall be accompanied by:

(a) the particulars and documentation:

(i)

referred to in points (1), (2), (3), (5) (11), to (9), (176) and (187) of Annex I;

(ii) the results of the pharmaceutical tests referred to in point 12(a) of Annex I;

(iii) the summary of product characteristics, without the clinical particulars

pharmacological properties as specified in Annex V. , unless necessary for the

safe use of the product;

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(iv) in case of combinations, as referred to in Article 4(1), point (64), or in Article

134(2), the information referred to in Article 134(1), first subparagraph, point (e),

relating to the combination as such; if the individual active substances are not

sufficiently known, the data shall also relate to the individual active substances;

(b) any national marketing authorisation or registration obtained by the applicant in another

Member State, or in a third country, to place the herbal medicinal product on the

market, and details of any decision to refuse to grant a national marketing authorisation

or registration, whether in the Union or a third country, and the reasons for any such

decision;

question, or a corresponding medicinal product has been in medicinal use throughout a

period of at least 30 years preceding the date of the application, including at least 15

years within the Union;

(d) a bibliographic review of safety data together with an expert report, and where required

by the competent authority of the Member State, upon additional request, data necessary

for assessing the safety of the herbal medicinal product.

For the purposes of the first subparagraph, point (c), at the request of the competent

authority of a Member State where the application for traditional-use registration has been

submitted, the herbal medicinal products working group shall draw up an opinion on the

adequacy of the evidence of the long-standing use referred to in the first subparagraph, point

(c), of the herbal medicinal product, or of the corresponding herbal medicinal product. The

competent authority of a Member State shall submit relevant documentation supporting the

referral.

For the purposes of the first subparagraph, point (d), in case of combinations, if the

individual active substances are not sufficiently known, the safety data referred to in the first

subparagraph, point (a)(iv), shall also relate to the individual active substances.

Annex II shall apply by analogy mutatis mutandis to the particulars and documentations

specified in the first subparagraph, point (a).

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The requirement to show medicinal use throughout the period of at least 30 years, set out in

paragraph 1, first subparagraph, point (c), is satisfied even where the marketing of the

corresponding herbal medicinal product has not been based on a specific marketing

authorisation. It is likewise satisfied where the number or quantity of ingredients of the

corresponding herbal medicinal product has been reduced during that period.

Where the herbal medicinalcorresponding product has been used in the Union for less than

15 years but is otherwise eligible for a traditional-use registration in accordance with

paragraph 1, the competent authority of the Member State where the application for

traditional-use registration has been submitted shall refer the application for the traditional

herbal medicinal product to the herbal medicinal products working group and submit relevant

documentation supporting this referral.

The herbal medicinal products working group shall consider whether the criteria other than

the period of transitional traditional use for a traditional-use registration as referred to in

Article 134 are complied with. If the herbal medicinal products working group considers it

possible, it shall establish a Union herbal monograph as referred to in Article 141(3) which

shall be taken into account by the competent authority of Member State when taking its final

decision on the application for the traditional use registration.

Article 137

Application of decentralised or mutual recognition to traditional herbal medicinal products

Chapter III, Sections 3 to 5, shall apply by analogy mutatis mutandis to traditional-use

registrations granted in accordance with Article 134, provided that:

(a) a Union herbal monograph has been established in accordance with Article 141(3); or

(b) the traditional herbal medicinal product consists of herbal substances, herbal

preparations or combinations thereof contained in the list referred to in Article 139.

For traditional herbal medicinal products not covered by paragraph 1, the competent authority

of each Member State shall, when evaluating an application for traditional-use registration,

take due account of registrations granted by the competent authority of another Member State

in accordance with this Section.

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Article 138

Refusal of registration of traditional herbal medicinal products

Traditional-use registration shall be refused if the application does not comply with Articles

134, 135 or 136 or if at least one of the following conditions is fulfilled:

(a) the qualitative or quantitative composition is not as declared;

(b) the therapeutic indications do not comply with the conditions laid down in Article 134;

use;

(d) the data on traditional use are insufficient, especially if pharmacological effects or

efficacy are not plausible on the basis of long-standing use and experience;

(e) the pharmaceutical quality is not satisfactorily demonstrated or inadequate.

The competent authorities of the Member States shall notify the applicant, the Commission

and any competent authority of the Member State that requests it, of any decision they take to

refuse traditional-use registration and the reasons for the refusal.

Article 139

List of herbal substances, herbal preparations and combinations thereof

The Commission shall adopt implementing acts to establish a list of herbal substances,

preparations and combinations thereof for use in traditional herbal medicinal products, taking

into account the draft list prepared by the herbal medicinal products working group. Those

implementing acts shall be adopted in accordance with the examination procedure referred to

in Article 214(2). The list shall contain, with regard to each herbal substance, the therapeutic

indication, the specified strength and the posology, the route of administration and any other

information necessary for the safe use of the herbal substance as a traditional herbal medicinal

product.

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If an application for traditional-use registration relates to a herbal substance, preparation or a

combination thereof contained in the list referred to in paragraph 1, the data specified in

Article 136(1), points (b), (c) and (d), shall not be required and Article 138(1), points (c) and

(d), shall not apply.

If a herbal substance, preparation or a combination is no longer included in the list referred to

in paragraph 1, registrations pursuant to paragraph 2 for herbal medicinal products containing

this substance shall be revoked unless the particulars and documentations referred to in

Article 136(1) are submitted within three months.

Article 140

Other requirements for traditional herbal medicinal products

Article 1(5), points (a) and (b) and Article 1(10), point (ac), Articles 6 5, 7, to 8, 29, 30, 44,

46, 56, 61, 89, 90, 92 155, 188, paragraphs 1 and 11, Articles 191, 195, 196, 197, 198, 199(2),

202, 203 and 204 and 206 and Chapters IV, IX, XI and XII and XV of this Directive as well

as Commission Directive (EU) 2017/1572432003/94/EC44 shall apply, mutadis mutandis, to

traditional-use registrations granted under this Section.

In addition to the requirements set out in Articles 63 to 66, 70 to 79 and Annex IV, any

labelling and package leaflet of a traditional herbal medicinal product shall contain a

statement to the effect that:

(a) the product is a traditional herbal medicinal product for use in specified therapeutic

indication(s) exclusively based upon long-standing use; and

(b) the user should consult a doctor or a qualified healthcare practitioner if the symptoms

persist during the use of the traditional herbal medicinal product or if adverse effects not

mentioned in the package leaflet occur.

Commission Directive (EU) 2017/1572 of 15 September 2017 supplementing Directive
2001/83/EC of the European Parliament and of the Council as regards the principles and
guidelines of good manufacturing practice for medicinal products for human use (OJ L 238,
16.9.2017, p. 44).

Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of
good manufacturing practice in respect of medicinal products for human use and investigational
medicinal products for human use (OJ L 262, 14.10.2003, p. 22).

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A Member State may require that the labelling and the package leaflet shall also state the

nature of the tradition in question.

In addition to the requirements set out in Chapter XIII, any advertisement for a traditional

herbal medicinal product registered under this Section shall contain the following statement:

Traditional herbal medicinal product for use in specified therapeutic indication(s) exclusively

based upon long-standing use.

Article 141

Herbal medicinal products working group

A herbal medicinal products working group is established as referred to in Article 142 of

[revised Regulation (EC) No 726/2004]. That working group shall be part of the Agency and

shall have the following competence:

(a) as regards traditional-use registrations, to:

(i)

perform the tasks arising from Article 136, paragraphs 1 and 3;

(ii) perform the tasks arising from Article 137;

(iii) prepare a draft list of herbal substances, preparations and combinations thereof, as

referred to in Article 139(1);

(iv) establish Union monographs for traditional herbal medicinal products, as referred

to in paragraph 3;

(b) as regards marketing authorisations of herbal medicinal products, to establish Union

herbal monographs for herbal medicinal products, as referred to in paragraph 3;

to traditional herbal medicinal products as referred to in Article 134, to perform the

tasks set out in Article 41;

(d) where a matter concerning medicinal products containing herbal substances or herbal

preparations, other than the traditional-use medicinal products, other medicinal

products containing herbal substances is referred to the Agency under Chapter III,

Section 5, or Article 95, to give an opinion on the herbal substance, where appropriate.

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Appropriate coordination with the Committee for Human Medicinal Products for Human Use

shall be ensured by a procedure to be determined by the Executive Director of the Agency in

accordance with Article 145(10) of [revised Regulation (EC) No 726/2004].

Each Member State shall appoint, for a three-year term which may be renewed, one member

and one alternate to the herbal medicinal working group.

The alternates shall represent and vote for the members in their absence. Members and

alternates shall be chosen for their role and experience in the evaluation of herbal medicinal

products and shall represent the competent authorities of the Member States.

The members of the herbal medicinal products working group may be accompanied by

experts in specific scientific or technical fields.

The herbal medicinal products working group shall establish Union herbal monographs for

herbal medicinal products with regard to the application submitted in accordance with of

Article 13 as well as traditional herbal medicinal products.

Where the Union herbal monographs have been established, they shall be taken into account

by the competent authorities of Member States when examining an application. Where no

such Union herbal monograph has yet been established, other appropriate monographs,

publications or data may be referred to.

When new Union herbal monographs are established, the traditional-use registration holder

shall consider whether it is necessary to modify the registration dossier accordingly. The

traditional-use registration holder shall notify any such modification to the competent

authority of the Member State concerned.

The herbal monographs shall be published.

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Provisions of Article 146, paragraphs 3 to 5 of the [revised Regulation (EC) No 726/2004]

applying to the working party shall apply by analogy mutatis mutandis to herbal medicinal

products working group.

The herbal medicinal products working group shall draft its rules of procedure.

Chapter XI

Manufacturing and import

Section 1

Manufacturing and import of medicinal products

Article 142

Manufacturing authorisation

Member States shall take all appropriate measures to ensure that the manufacture of the

medicinal products within their territory is subject to authorisation (the “manufacturing

authorisation”). The manufacturing authorisation shall be required also if the medicinal

products manufactured are intended for export.

The manufacturing authorisation referred to in paragraph 1 shall be required for both total and

partial manufacture, and for the various processes of dividing up, packaging or presentation.

The manufacturing authorisation shall apply only to the categories of medicinal

products, pharmaceutical forms, the manufacturing operations and the premises

specified in the application.

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By derogation from paragraph 2, the manufacturing authorisation shall not be required for the

following:

(a) preparation, dividing up, changes in packaging or presentation where these processes

are carried out, solely for retail supply, by pharmacists in dispensing pharmacies or by

persons legally authorised in the Member States to carry out such processes; or

(b) decentralised sites carrying out manufacturing or testing steps, in accordance with

Article 26a and Article 148, under the responsibility of the qualified person of a

central site referred to in Article 151(3).

A manufacturing authorisation shall also be required for imports of medicinal products

coming from third countries into a Member State.

This Chapter and Articles 195(5) and 198 shall apply to imports of medicinal products from

third countries.

Member States shall enter the information relating to the manufacturing authorisation referred

to in paragraph 1 in the Union database referred to in Article 188(15).

Article 143

Requirements for a manufacturing authorisation

In order to obtain the manufacturing authorisation, the applicant shall submit an application

by electronic means to the competent authority of the Member State concerned. Member

States may provide for the possibility of submission in paper format.

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That application shall include at least the following particulars:

(-a) name or corporate name and permanent address;

(a) the medicinal products, the pharmaceutical forms and the manufacturing operations that

are to be manufactured, imported or carried out and the place where the activity will

take place;

(b) proof that the applicants have at their disposal, for the manufacture or import of the

above, suitable and sufficient premises, technical equipment and control facilities

complying with the legal requirements that the Member State concerned lays down as

regards both manufacture and control and the storage of medicinal products, in

accordance with Article 8;

person within the meaning of Article 151;

(d) explanation on whether the site is the central site responsible for the oversight of

decentralised sites.

1a. In the case of an application for a central site responsible for decentralised

manufacturing, the particulars referred to in paragraph 1 shall also include:

(a) proof that that the use of decentralised manufacturing has been referenced in the

marketing authorisation application in accordance with Article 26a for the

medicinal product(s) concerned;

(b) description of the medicinal product(s) that are subject to manufacturing steps in

the decentralised sites, including the manufacturing or testing activities to be

performed for those medicinal products at the decentralised sites;

(c) proof that the applicants have at their disposal appropriate procedures and

resources for the oversight of decentralised sites in accordance with Article 147(1),

first subparagraph, point (f);

(d) for each decentralised site at the time of the application, a written confirmation by

the qualified person referred to in Article 151(3) that the applicant has verified its

compliance with principles and guidelines of good manufacturing practice referred

to in Article 160 by conducting an audit.

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The applicant shall provide, by electronic means, particulars in support of the above in their

application. Member States may provide for the possiblity of a submission in paper

format.

Article 144

Granting of a manufacturing authorisation

The official representatives of the competent authority of the Member State concerned shall

carry out an inspection to ensure the accuracy of the particulars included in the application

submitted in accordance with Article 143.

Where the accuracy of the particulars is confirmed in accordance with the first subparagraph,

or in any event, and no later than 90 days after the receipt of the application submitted in

accordance with Article 143, the competent authority of the Member State shall grant or

refuse a manufacturing authorisation.

By way of derogation from the second subparagraph, in justified cases, the inspection

may be carried out after the manufacturing authorisation has been granted.

To ensure that the particulars referred to in Article 143 are duly submitted, the competent

authority of the Member State may grant a manufacturing authorisation subject to conditions.

For central sites, a manufacturing authorisation shall include for each decentralised site

a written confirmation that the manufacturer of the medicinal product has verified compliance

of the decentralised site with principles of good manufacturing practice referred to in Article

160 by conducting regular audits in accordance with Article 147(1), first subparagraph, point

(f).

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The manufacturing authorisation shall apply only to the medicinal products, pharmaceutical

forms, the manufacturing operations and the premises specified in the application and to the

premises of the corresponding central site where decentralised manufacturing or testing

activities are carried out in decentralised sites, which are registered in accordance with Article

148.

Article 145

Changes in a manufacturing authorisation

If the manufacturing authorisation holder requests a change in any of the particulars referred to in

Article 143(1) and (1a) points (a), (b) and (c), second subparagraph, the competent authority of the

Member State shall take a decision on the requested amendment of the manufacturing

authorisation no later than 30 days from such request. In exceptional cases this period of time may

be extended to 90 days.

Article 146

Request for additional information

The competent authority of the Member State may request the applicant to submit additional

information on the particulars supplied pursuant to Article 143(1) and on the qualified person

referred to in Article 151; where the competent authority of the Member State makes such request,

the time limits referred to in Articles 144(1), second subparagraph, and 145 shall be suspended until

the additional information has been supplied.

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Article 147

Obligations of the manufacturing authorisation holder

Member States shall ensure that manufacturing authorisation holders shall:

(a) have at their disposal the services of staff who comply with the legal requirements

existing in the Member State both as regards manufacture and controls;

(b) dispose of the medicinal products that have been granted a marketing authorisation only

in accordance with the legislation of the Member States;

may wish to make to any of the particulars provided in accordance to Article 143;

(d) allow the official representatives of the competent authority of the Member State access

to their premises and, where sites carry out manufacturing or testing activities in

connection with a central site in the decentralised site, to the premises of the central or

the decentralised sites at any time;

(e) enable the qualified persons referred to in Article 151 to carry out their duties, where

appropriate applicable also in decentralised sites, for example by placing at their

disposal all the necessary resources and ensuring their access to the premises,

including relevant electronic systems and documentation of the decentralised

site(s);

(f)

comply, in any relevant site and at all times with the principles of good manufacturing

practice for medicinal products;

(g) use only active substances that have been manufactured in accordance with good

manufacturing practice for active substances and distributed in accordance with good

distribution practices for active substances;

(h) inform the competent authority of the Member State and the marketing authorisation

holder immediately if they obtain information that medicinal products that come under

the scope of their manufacturing authorisation are, or are suspected of being, falsified

irrespective of the way the medicinal products were distributed;

(i)

verify that the manufacturers, importers or distributors from whom they obtain active

substances are registered with the competent authority of the Member State in which

they are established; and

(j)

verify the authenticity and quality of the active substances and the excipients.

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As regards the first subparagraph, point (c), the competent authority of the Member State

shall, in any event, be immediately informed if the qualified person referred to in Articles

143(1), point (c), and 151 is replaced unexpectedly.

For the purposes of points (f) and (g), manufacturing authorisation holders shall verify

compliance, respectively, by the manufacturer or distributors of active substances with good

manufacturing practice and good distribution practices respectively, by conducting regular

audits at the manufacturing and distribution sites of the manufacturer and distributors of

active substances. Manufacturing authorisation holders shall verify such compliance either by

themselves or through an entity acting on their behalf under a contract. Manufacturing

authorisation holders shall verify such compliance either by themselves or through an entity

acting on their behalf under a contract.

The manufacturing authorisation holder shall ensure that the excipients are suitable for use in

medicinal products by ascertaining the appropriate good manufacturing practice on the basis

of a formalised risk assessment.

The manufacturing authorisation holder shall ensure that the appropriate good manufacturing

practice ascertained in accordance with paragraph 2, is applied. The manufacturing

authorisation holder shall document the measures taken in accordance with paragraphs 1 and

Article 148

Registration and listing process of supervision of decentralised sites

The manufacturing authorisation holder of the central site shall register all of its decentralised

sites in accordance with the provisions of this Article.

The manufacturing authorisation holder of the central site shall request the competent

authority of the Member State in which the decentralised site is established, to register the

decentralised site.

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The competent authority of the Member State where the decentralised site is located

shall not register the decentralised manufacturing site until it has been established as

part of a marketing authorisation application that the use of decentralised

manufacturing is justified in accordance with Article 26a paragraph.

The marketing authorisation holder may commence the activity in the decentralised site in

connection with the central site only when the decentralised site is registered in the Union

database referred to in Article 188(15) and the link is made in the database with the

authorisation of the corresponding central site by the competent authority of the Member state

where the decentralised site is located.

The marketing authorisation holder shall ensure that all the activities at the central and

decentralised sites are carried out in compliance with the delegated acts referred to in

Articles 160 and 161 and the marketing authorisation referred to in Article 26a.

The manufacturing authorisation holder may commence the activity in the decentralised

site in connection with the central site only when the marketing authorisation holder has

ensured that:

(a) the central site is authorised by the competent authority of the Member Sstate

where it is located;

(b) the decentralised site is registered by the competent authority of the Member

Sstate where it is located; and

(c) the registration of the decentralised site is referenced with the authorisation of the

corresponding central site by the competent authority of the Member State where

the central site is located; in the Union database referred to in Article 188(15).

The competent authority of the Member State in which the decentralised site is established, is

responsible, in accordance with Article 188, for the supervision of the manufacturing and

testing activities carried out in the decentralised site.

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For the purpose of paragraph 2 the manufacturing authorisation holder of the central site shall

submit a registration form that shall include, at least, the following information:

(a) name or corporate name and permanent address of the decentralised site, and a proof of

its establishment in the Union and the name and contact details of a person

designated as the local contact for the decentralised site along with a written

confirmation of the decentralised site that it supports the application for

registration;

(b) the pharmaceutical forms and the medicinal products that are subject to

manufacturing or testing steps in the decentralised site, including the manufacturing or

testing activities to be performed for those medicinal products and the reference to the

relevant marketing authorisation or the marketing authorisation application

referred to in Article 26a, paragraph 1;

to carry out the relevant activities;

(d) the reference to the manufacturing authorisation of the central site;

(e) the written confirmation by the qualified person referred to in Article 151(3)referred

to in Article 144(2), second subparagraph, that the manufacturing authorisation holder

er of the medicinal product has verified compliance of the decentralised site with

principles of good manufacturing practice referred to in Article 160 by conducting

audits; the latest audit reports shall be submitted if the competent authority of the

Member State in which the decentralised site is established so requests;

(f)

proof that the appropriate resources are available at the central site for the

qualified person referred to in Article 151 to carry out the tasks referred to in

Article 153(4) regarding the supervision of the decentralised site.

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The competent authority of the Member State supervising the decentralised site pursuant to

paragraph 4 may decide to carry out an inspection as referred to in Article 188(1), first

subparagraph, point (a). In such cases, that competent authority shall cooperate with the

competent authority of the Member State responsible for the supervision of the central site.

The competent authority of the Member State shall have access to the premises of the

decentralised site. If the outcome of the inspection shows that the applicant does not

comply with the principles of good manufacturing practices as referred to in Article 160,

the competent authority shall not register that entity in the Union database referred to

in Article 188(15) or if that entity is already registered in the Union database referred to

in Article 188(15), it shall remove the entity from this database.

Following the registration of the decentralised site pursuant to paragraph 2, the manufacturing

authorisation holder of the central site shall list the registered decentralised site in the

manufacturing authorisation of the central site.

The competent authority of the Member State supervising the decentralised site pursuant to

paragraph 4 shall cooperate with the relevant authorities responsible for the supervision of the

manufacturing or testing activities under other Union acts as regards the following:

(a) the medicinal products that were manufactured in a decentralised site, the testing or

manufacturing of which involves using raw material, medicinal products regulated

under other relevant Union law, or medicinal products that are intended to be combined

with medical devices;

(b) where specific manufacturing or testing activities are applied to the medicinal products

containing, consisting or derived from SoHO for which specific manufacturing or

testing activities are applied within a decentralised site that is also authorised under

[SoHO Regulation] Regulation (EU) 2024/1938. Such co-operation shall include

sharing information about any unilateral actions in relation to the decentralised

site resulting from their respective responsibilities.

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The respective competent authorities of the Member States supervising the central and

decentralised sites shall cooperate and exchange information as regards the

authorisation of the central site, the regisitration of the decentralised site(s) and their

supervision.

Where relevant appropriate, competent authorities of the Member States supervising the

central and decentralised sites may liaise with the competent authority of the Member State

responsible for the supervision of the marketing authorisation. and the Agency or the

competent authority of the Member State responsible for the supervision of the

marketing authorisation shall cooperate and exchange information. Where the

supervisory authority detects any deficiency in the central site or the decentralised sites

that may impact the quality or safety of the medicinal product concerned, it shall inform

the relevant national competent authorities or the Agency without undue delay.

10. In case of any situation having an impact on the quality or safety of the medicinal

products that are manufactured or tested at the decentralised site, the marketing

authorisation holder and the qualified person of the central site shall inform the

competent authorities supervising the central and decentralised sites, and the competent

authorities supervising the marketing authorisation respectively without undue delay, in

order to take the appropriate actions.

11. The competent authority of the Member State where the decentralised site is located

may suspend or revoke the registration of the decentralised site, fully or partially, as

appropriate, if the conditions set out in paragraph 2 to 5 cease to be met. In such an

event the competent authority of the Member State shall without undue delay inform

the competent authorities referred to in paragraph 9.

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Article 149

Conditions related to the safety features

The safety features referred to in Annex IV shall not be removed or covered, either fully or

partially, unless the following conditions are fulfilled:

(a) the manufacturing authorisation holder verifies, prior to partly or fully removing or

covering those safety features, that the medicinal product concerned is authentic and

that it has not been tampered with;

(b) the manufacturing authorisation holder complies with Annex IV by replacing those

safety features with safety features that are equivalent as regards the possibility to verify

the authenticity, identification and to provide evidence of tampering of the medicinal

product. Such replacement shall be conducted without opening the immediate

packaging.

Safety features shall be considered equivalent if they:

(i)

comply with the requirements set out in the delegated acts adopted pursuant to

Article 67(2); and

(ii) are equally effective in enabling the verification of authenticity and identification

of medicinal products and in providing evidence of tampering with medicinal

products;

manufacturing practice for medicinal products; and

(d) the replacement of the safety features is subject to supervision by the competent

authority of the Member State.

Manufacturing authorisation holders, including those performing the activities referred to in

paragraph 1, shall be regarded as producers and therefore held liable for damages in the cases

and under the conditions set forth in Directive 85/374/EEC.

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Article 150

Potentially falsified medicinal products

By derogation from Article 1(2), and without prejudice to Chapter XII, Section 1, Member

States shall take the necessary measures in order to prevent medicinal products that are

introduced into the Union, but are not intended to be placed on the market in the Union, from

entering into circulation if there are sufficient grounds to suspect that those products are

falsified.

Member States shall organise meetings involving patients’ and consumers’ organisations and,

as necessary, Member States’ enforcement officers, in order to communicate public

information about the actions undertaken in the area of prevention and enforcement to combat

the falsification of medicinal products. Member States shall communicate public

information about the actions undertaken in the area of prevention and enforcement to

combat the falsification of medicinal products involving patients’ and consumers’

organisations and, as necessary, Member States’ enforcement officers.

In order to establish what the necessary measures referred to in paragraph 1 are the

Commission is empowered to adopt delegated acts in accordance with Article 215, to

supplement paragraph 1 by specifying the criteria to be considered and the verifications to be

made when assessing the potential falsified character of medicinal products introduced into

the Union but not intended to be placed on the market.

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Article 151

Availability of qualified person

Member States shall take all appropriate measures to ensure that the manufacturing

authorisation holder has permanently and continuously at their disposal the services of at least

one qualified person residing and operating in the Union, in accordance with the conditions

laid down in Article 152, responsible in particular for carrying out the duties specified in

Article 153.

A manufacturing authorisation holder who is a natural person and personally fulfils the

conditions laid down in Annex III may assume the responsibility referred to in paragraph 1.

Where the manufacturing authorisation is granted to a central site specified in the application

pursuant to Article 144(3), the qualified person referred to in paragraph 1 shall also be

responsible for carrying out the duties specified in Article 153(4) regarding the decentralised

sites. For this purpose, the available resources for the services referred to in paragraph 1

at a central site shall be commensurate with the number of decentralised sites and their

activity.

Article 152

Qualification of qualified person

Member States shall ensure that the qualified person referred to in Article 151 fulfils the

conditions of qualification set out in Annex III.

The manufacturing authorisation holder and the qualified person shall ensure that the practical

experience acquired is appropriate to the types of products to be certified.

The competent authority of the Member State may lay down appropriate administrative

procedures to verify that a qualified person referred to in the paragraph 1 fulfils the conditions

set out in Annex III.

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Article 153

Responsibilities of the qualified person

Member States shall take all appropriate measures to ensure that the qualified person referred

to in Article 151, without prejudice to their relationship with the manufacturing authorisation

holder, are responsible, subject to the procedures referred to in Article 154, for securing:

(a) in the case of medicinal products manufactured within the Member States concerned,

that each production batch of medicinal products has been manufactured and checked in

compliance with the laws in force in that Member State and in accordance with the

requirements of the marketing authorisation;

(b) in the case of medicinal products imported from third countries, irrespective of whether

they have been manufactured in the Union that each production batch has undergone in

a Member State a full qualitative analysis, a quantitative analysis of at least all the

active substances and all the other tests or checks necessary to ensure the quality of the

medicinal products in accordance with the requirements of the marketing authorisation.

The qualified person referred to in Article 151 shall in the case of medicinal products intended

to be placed on the Union market, ensure that the safety features referred to in Annex IV have

been affixed on the packaging.

The batches of medicinal products that have undergone the controls referred to in the first

subparagraph, point (b), in a Member State shall be exempt from those controls if they are

marketed in another Member State, accompanied by the control reports signed by the

qualified person.

In the case of medicinal products imported from a third country, where appropriate

arrangements have been made by the Union with the exporting country to ensure that the

manufacturer applies standards of good manufacturing practice at least equivalent to those

laid down by the Union, and to ensure that the controls referred to in paragraph 1, first

subparagraph, point (b), have been carried out in the exporting country, the qualified person

may be relieved of responsibility for carrying out those controls.

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In all cases and particularly where the medicinal products are released for sale, the qualified

person shall certify in a register or equivalent format provided for that purpose, that each

production batch satisfies the provisions of this Article; that register or equivalent format shall

be kept up to date during the time when operations are carried out and shall remain at the

disposal of the official representatives of the competent authority of the Member State for the

period specified in the provisions of the Member State concerned and in any event for at least

five years.

For the purposes of Article 151(3), the qualified person shall, in addition:

(a) supervise that the manufacturing or testing activities carried out at the decentralised

sites comply with principles of relevant good manufacturing practices referred to in

Article 160 and conform to the marketing authorisation;

(b) conduct regular audits, including periodic on-site visits, at the decentralised sites

and provide a written confirmation as referred to in Article 144(2), second

subparagraph that the holder of the manufacturing authorisation for the central site

has verified compliance of the decentralised site with principles of good

manufacturing practice referred to in Article 160;

site is established, an inventory of the changes that have taken place as regards the

information provided in the registration form submitted pursuant to Article 148(5).

Any changes that may have an impact on the quality or safety of the medicinal products

that are manufactured or tested at the decentralised site must be notified immediately.

The Commission is empowered to adopt a delegated act in accordance with Article 215 to

supplement the first subparagraph, point (c), specifying the notification made by the qualified

person.

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Article 154

Professional code of conduct

Member States shall ensure that the duties of qualified persons referred to in Article 151 are

fulfilled, either by means of appropriate administrative measures or by making such persons

subject to a professional code of conduct.

Member States may provide for the temporary suspension of a qualified person referred to in

Article 151 upon the commencement of administrative or disciplinary procedures against that

qualified person for failure to fulfil its duties set out in Article 153. The suspension of a

qualified person applies to all manufacturing authorisations concerned.

In the case of decentralised manufacturing, the supervisory authorities of the central site

and of the decentralised sites, if different, shall cooperate to implement for the measures

referred to paragraphs 1 and 2.

Article 155

Certificate for export of a medicinal product

At the request of the manufacturer, the marketing authorisation holder, the exporter or the

competent authorities of an importing third country, the competent authority of the Member

States shall certify issue a certificate for export that a manufacturer of medicinal products is

in possession of a manufacturing authorisation or refer to the manufacturing authorisation

and the GMP certificate available in the database referred to in Article 188(15).

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1a. When issuing such certificates For the purposes of paragraph 1, the competent authority

of the Member States shall:

(a) comply with the prevailing administrative arrangements of the World Health

Organization;

(b) for medicinal products intended for export that are already authorised in their

territory, supply the summary of product characteristics as approved by them in

accordance with Article 43 or, as appropriate, refer to the summary of product

characteristics they made publicly available.

When the manufacturer is not in possession of a marketing authorisation it shall provide the

competent authorities responsible for issuing the certificate referred to in paragraph 1, with a

declaration explaining why a marketing authorisation is not available.

Section 2

Manufacturing, import and distribution of active substances

Article 156

Manufacture of active substances

For the purposes of this Directive, manufacture of active substances used in the manufacturing

process of a medicinal product shall include both total and partial manufacture or import of an

active substance and the various processes of dividing up, packaging or presentation prior to its

incorporation into a medicinal product, including repackaging or re-labelling, such as are carried

out by a distributor of active substances.

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Article 157

Registration of importers, manufacturers and distributors of active substances

Importers, manufacturers and distributors of active substances who are established in the

Union shall register their activity with the competent authority of the Member State in which

they are established.

The registration form, to be submitted by electronic means, shall include, at least, the

following information:

(a) name or corporate name and permanent address;

(b) the active substances that are to be imported, manufactured or distributed;

Member States may provide for the possiblity of a paper form submission.

The persons referred to in paragraph 1 shall submit, by electronic means, the registration form

to the competent authority of the Member State at least 60 days prior to the intended

commencement of their activity. Member States may provide for the possiblity of a paper

form submission.

The competent authority of the Member State may, based on a risk assessment, decide to

carry out an inspection. If the competent authority of the Member State notifies the applicant

within 60 days of the receipt of the registration form that an inspection will be carried out, the

activity shall not begin before the competent authority of the Member State has notified the

applicant that they may commence the activity. If within 60 days of the receipt of the

registration form the competent authority of the Member State has not notified the applicant

that an inspection will be carried out, the applicant may commence the activity.

4a. If the outcome of the inspection carried out in accordance with paragraph 4 shows that

the applicant does not comply with the principles of good manufacturing practice or

good distribution practices for active substances as referred to in Article 160, the

competent authority shall not register that entity in the Union database referred to in

Article 188(15).

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Annually, the persons referred to in paragraph 1 shall communicate, by electronic means, to

the competent authority of the Member State an inventory of the changes that have taken

place as regards the information provided in the registration form. Any changes that may have

an impact on the quality or safety of the active substances that are manufactured, imported or

distributed must be notified immediately.

The comptetent authority of the Member State shall enter the information provided in

accordance with paragraph 2 in the Union database referred to in Article 188(15).

The competent authority of the Member State may suspend or revoke the registration of

the site fully or partially, as appropriate, if the conditions set out in paragraph 2 and

Article 158(1) cease to be met. In such an event the competent authority of the Member

State shall without undue delay inform the competent authorities of other Member

States and the Agency.

Article 158

Conditions for importing active substances

Member States shall take appropriate measures to ensure that the manufacture, import and

distribution on their territory of active substances, including active substances that are

intended for export, comply with the principles of good manufacturing practice and good

distribution practices for active substances specified in the delegated acts adopted in

accordance with Article 160.

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Active substances shall only be imported if the following conditions are fulfilled:

(a) the active substances have been manufactured in accordance with the principles of good

manufacturing practices at least equivalent to those laid down by the Union pursuant to

Article160; and

(b) the active substances are accompanied by a written confirmation issued by the

competent authority of the exporting third country stating that:

(i)

the principles of good manufacturing practices applicable to the manufacturing

site manufacturing the exported active substance are at least equivalent to those

laid down by the Union pursuant Article 160;

(ii) the manufacturing site concerned is subject to regular, strict and transparent

controls and to the effective enforcement of good manufacturing practice,

including repeated and unannounced inspections, so as to ensure a protection of

public health at least equivalent to that in the Union; and

(iii) in the event of findings relating to non-compliance, information on such findings

is supplied by the exporting third country to the Union without undue delay.

The conditions set out in paragraph 2, point (b), shall not apply if the exporting country is

included in the list referred to in Article 159(2).

The conditions set out in paragraph 2, point (b), may be waived by any competent authority of

a Member State for a period not exceeding the validity of the certificate of good

manufacturing practice issued in accordance with Article 188(13) where a site manufacturing

an active substance for export has been inspected by the competent authority of a Member

State and was found to comply with the principles of good manufacturing practice laid down

pursuant to Article160.

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Article 159

Active substances imported from third countries

At the request of a third country, the Commission shall assess whether that country’s

regulatory framework applicable to active substances exported to the Union and the respective

control and enforcement activities ensure a level of protection of public health equivalent to

that of the Union.

The assessment shall take the form of a review of relevant documentation submitted by

electronic means and, unless arrangements as referred to in Article 153(2) are in place that

cover this area of activity, that assessment shall include an on-site review of the third

country’s regulatory system and, if necessary, an observed inspection of one or more of the

third country’s manufacturing sites for active substances.

Based on the assessment referred to in paragraph 1, the Commission may adopt implementing

acts to include the third country in a list and to apply the requirements set out in the second

subparagraph. Those implementing acts shall be adopted in accordance with the examination

procedure referred to in Article 214(2).

When assessing the third country pursuant to paragraph 1, the Commission shall take account

of the following:

(a) the country’s rules for good manufacturing practice;

(b) the regularity of inspections to verify compliance with good manufacturing practice;

(d) the regularity and rapidity of information provided by the third country relating to non-

compliant manufacturers of active substances.

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The Commission shall verify regularly whether the conditions laid down in paragraph 1 are

fulfilled. The first verification shall take place no later than 3 years after the third country has

been included in the list referred to in paragraph 2.

The Commission shall perform the assessment referred to in pargarph 1 and verification

referred to in paragraph 3 in cooperation with the Agency and the competent authorities of the

Member States.

Section 3

Principles of good manufacturing and good distribution practices

Article 160

Rules applicable to medicinal products and active substances

The Commission may shall adopt implementing delegated acts in accordance with Article 2154(2)

to supplement this Directive by specifying:

(a) the principles of good manufacturing and good distribution practices for medicinal products

complemented, where relevant, by specific measures applicable notably to pharmaceutical

forms, medicinal products or manufacturing activities in line with good manufacturing

principles;

(b) the principles of good manufacturing and good distribution practices for active substances

The Agency, in particular through its inspection working group referred to in Article 142(k)

of [the revised Regulation (EU) 726/2004], in agreement with the Commission, shall draw up

guidelines on good manufacturing and distribution practices, including guidelines specific to

advanced therapy medicinal products.

Where relevant, these principles shall be specified in coherence with any principles of good

practices established under any other Union legal framework.

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Article 161

Rules applicable to excipients

The Commission is empowered to adopt delegated acts in accordance with Article 215 to

supplement this Directive on the formalised risk assessment for ascertaining the appropriate good

manufacturing practice for excipients referred to in Article 147(2). Such risk assessment shall take

into account requirements under other appropriate quality systems as well as the source and

intended use of the excipients and previous instances of quality defects.

Chapter XII

Wholesale distribution and sale at a distance

Section 1

Wholesale distribution and brokering of medicinal products

Article 162

Wholesale distribution of medicinal products

Without prejudice to Article 5, Member States shall take all appropriate action to ensure that

only medicinal products in respect of which a marketing authorisation has been granted in

accordance with Union law are distributed on their territory.

In the case of wholesale distribution including storage, medicinal products shall be covered by

either a centralised marketing authorisation or by a national marketing authorisation.

Wholesale Ddistributors who intend to import obtain a medicinal product from another a

source Member State shall notify the marketing authorisation holder and the competent

authority of the destination Member State to which the medicinal product is to be imported of

their intention to import distribute that medicinal product in the destination Member State.

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3a. Member States shall ensure that the wholesale distributor demonstrates that the

medicinal product obtained from a Member State (‘source Member State’) and

distributed in another Member State (‘destination Member State’) is already covered by

a marketing authorisation in the destination Member State, including demonstrating

that the medicinal products share a common origin. A Member State may set additional

requirements whose fulfilment it considers necessary to demonstrate that the medicinal

product authorised in the source Member State and the medicinal product authorised in

the destination Member State may be reasonably considered the same product.

The destination Member State shall refuse to permit the parallel trade of a medicinal

product by a wholesale distributor from the source Member State in case they consider

that permitting such parallel trade would circumvent the mutual recognition procedure

as referred to in Chapter III.

In the case of medicinal products covered by a national marketing authorisation, the

notification referred to in paragraph 3 to the competent authority of the Member State shall be

without prejudice to additional procedures provided for in the legislation of that Member State

and to fees payable to the competent authority of the Member State for examining the

notification. A Member State may require that the imported medicinal product is

labelled in accordance with Article 74. The Member State may also require that the

electronic product information is provided in accordance with Article 63(3).

In the case of medicinal products covered by a centralised marketing authorisation, the

wholesale distributor shall submit the same notification referred to in paragraph 3 to the

Agency which will be in charge of checking that the conditions laid down in Union law on

medicinal products and in the marketing authorisations are observed. For this check, a fee

shall be payable to the Agency.

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Article 163

Authorisation for wholesale distribution of medicinal products

The competent authority of the Member State concerned shall take all appropriate measures to

ensure that the wholesale distribution of medicinal products is subject to an authorisation to

engage in activity as a wholesaler in medicinal products (“wholesale distribution

authorisation”). The wholesale distribution authorisation shall indicate the premises, the

categories of medicinal products and the wholesale distribution operations for which it is

valid.

Where persons authorised or entitled to supply medicinal products to the public may also,

under national law, engage in wholesale business, such persons shall be subject to the

authorisation provided for in paragraph 1.

A manufacturing authorisation required under Article 142 shall include an authorisation to

distribute by wholesale the medicinal products that it covers. A wholesale distribution

authorisation shall not give dispensation from the obligation set out in Article 142 to hold a

manufacturing authorisation and to comply with the conditions set out in that respect, even

where the manufacturing or import business is secondary.

The competent authority of the Member State concerned shall enter the information relating to

the wholesale distribution authorisations in the Union database referred to in Article 188(15).

The competent authority of the Member State that granted the wholesale distribution

authorisation for premises located in its territory shall ensure that controls of the persons

authorised to engage in activity as a wholesaler in medicinal products, and inspections of their

premises, are carried out at an appropriate frequency.

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The competent authority of the Member State that granted the wholesale distribution

authorisation shall suspend or revoke it if the conditions for granting it set out in Article 162

cease to be met or if the obligations set out in Article 166 are not being fulfilled. In such

event the Member State shall without undue delay inform the other Member States and the

Commission thereof.

Where a competent authority of a Member State considers that the conditions for granting a

wholesale distribution authorisation set out in Article 1642 are not met with respect to a

wholesale distribution authorisation granted by the competent authority of another Member

State, it shall without undue delay inform the Commission and the competent authority of the

other Member State thereof. The competent authority of the other Member State shall take the

measures it considers necessary and shall inform the Commission and the competent authority

of the first Member State of those measures and the reasons for them.

Article 164

Requirements for a wholesale distribution authorisation

In order to obtain a wholesale distribution authorisation, applicants shall submit an application

by electronic means to the competent authority of the Member State concerned. Member

States may provide for the possiblity of a paper form submission.

The application referred to in paragraph 1 shall include at least the following particulars:

(a) a confirmation and proof that the applicants have a permanent address in the Member

State and have at their disposal suitable and adequate premises, installations and

equipment, to ensure proper conservation and distribution of the medicinal products;

(b) a confirmation and proof that the applicants have at their disposal appropriately trained

staff, and in particular, a qualified person designated as responsible, meeting the

conditions provided for by the legislation of the Member State concerned; a responsible

person, meeting the qualifications and conditions provided for by the legislation of

the Member State;

166.

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Article 165

Granting of a wholesale distribution authorisation

The official representatives of the competent authority of the Member State concerned shall

shall carry out an inspection to confirm the accuracy of the particulars provided in accordance

with Article 164.

By way of derogation from the second subparagraph, in justified cases, the inspection

may be carried out after the wholesale distribution authorisation has been granted.

Where the accuracy of the particulars is confirmed in accordance with the first subparagraph

and, or in any event, no later than 90 days after the receipt of the application submitted in

accordance with Article 164, the competent authority of the Member State shall grant or

refuse a wholesale distribution authorisation.

The competent authority of the Member State concerned may require the applicant to supply,

by electronic means, all necessary information concerning the particulars for granting the

wholesale distribution authorisation. In such case, the period laid down in paragraph 1 shall

be suspended until the requisite additional information is supplied.

Member States may provide for the possiblity of submission of the information referred

to in the first subparagraph in paper format.

The competent authority of the Member State may grant a wholesale distribution

authorisation subject to conditions.

The wholesale distribution authorisation shall apply only to the wholesale distribution

activites, categories of medicinal products and the premises specified in the authorisation.

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Article 166

Obligations of the wholesale distribution authorisation holder

Member States shall ensure that wholesale distribution authorisation holders shall:

(a) have at their disposal the services of staff who comply with the legal requirements

existing in the Member State as regards wholesale distribution;

(b) allow the official representatives of the competent authority of the Member State access

to their premises, installations and equipment referred to in Article 164(2), point (a), at

all times;

only from persons who are themselves in possession of a wholesale distribution

authorisation in the Union or a manufacturing authorisation referred to in Article

163(3);

(d) supply, including by financial transaction, medicinal products only to persons who are

themselves wholesale distribution authorisation holders or who are authorised or

entitled to supply medicinal products to the public;

(e) verify that the medicinal products received are not falsified by checking the safety

features on the outer packaging, in accordance with the requirements laid down in the

delegated acts adopted pursuant to Article 67(2), second subparagraph;

(f)

have an emergency plan that ensures effective implementation of any recall from the

market ordered by the competent authorities or carried out in cooperation with the

manufacturer or marketing authorisation holder for the medicinal product concerned;

(g) keep records giving, for any medicinal products received, dispatched or brokered, at

least the following information:

(i)

the date of receipt, dispatch or brokering of the medicinal product,

(ii) the name of the medicinal product,

(iii) the quantity of the medicinal product received, supplied or brokered,

(iv) the name and address of the supplier of the medicinal product or the consignee, as

appropriate,

(v) the batch number of the medicinal products, at least for medicinal products

bearing the safety features referred to in Article 67;

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(h) keep the records referred to in point (g) available to the competent authorities of the

Member States, for inspection supervision purposes, for a period of five years;

(i)

comply with the principles of good distribution practices for medicinal products laid

down in Article 160;

(j)

maintain a quality system setting out responsibilities, processes and risk management

measures in relation to their activities;

(k) immediately inform the competent authority of the Member State and, where applicable,

the marketing authorisation holder, of medicinal products they receive or are offered

that they identify as falsified or suspect to be falsified;

(l)

continuously guarantee, within the limits of their responsibility, the appropriate and

continued supply of an adequate suitable range of medicinal products to meet the

requirements of a specific geographical area, and deliver the supplies requested over the

whole of the area in question, within a reasonable timeframe, which shall be defined in

accordance with the requirements of the national legislation;

(m) cooperate with marketing authorisation holders and competent authorities of the

Member States on the security of supply referred to in Chapter X of [revised

Regulation];

(ma) cooperate with marketing authorisation holders and competent authorities of the

Member States on monitoring and management of shortages and critical shortages

referred to in Chapter X of [revised Regulation].

Where the medicinal product is obtained from another wholesale distributor, the wholesale

distribution authorisation holders obtaining the product shall verify compliance with the

principles of good distribution practices by the supplying wholesale distributor. This includes

verifying whether the supplying wholesale distributor holds a wholesale distribution

authorisation, or a manufacturing authorisation referred to in Article 163(3).

Where the medicinal product is obtained from a manufacturer or importer, wholesale

distribution authorisation holders shall verify that the manufacturer or importer holds a

manufacturing authorisation.

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Where the medicinal product is obtained through brokering of medicinal products, wholesale

distribution authorisation holders shall verify that the person brokering the medicinal product

fulfils the requirements set out in Article 171.

In respect of a medicinal product where the protection referred to in Article 80,

paragraph (2) or the prolongation referred to in Article 72(2) of [revised Regulation

726/2004] does not apply in a Member State pursuant to Article 56a(5), the wholesale

distribution holder or any person or entity engaged in sale at a distance of medicinal

products shall not make the generic, biosimilar, hybrid and biohybrid medicinal

product available on the market of another Member State where the protection referred

to in Article 80 paragraph (2) and, if applicable, Article 72(2) of [revised Regulation

726/2004] applies, during the period of the protection.

Article 167

Obligation of supply of medicinal products

With regard to the supply of medicinal products to pharmacists and persons authorised or

entitled to supply medicinal products to the public, Member States shall not impose upon the

wholesale distribution authorisation holder that has been granted by another Member State

any obligation, in particular public service obligations, more stringent than those they impose

on persons whom they have themselves authorised to engage in equivalent activities.

The wholesale distributors of a medicinal product placed on the market in a Member State

shall, within the limits of their responsibilities, ensure appropriate and continued supplies of

that medicinal product to pharmacies and persons authorised to supply medicinal products so

that the needs of patients in the Member State in question are covered.

The arrangements for implementing this Article should, moreover, be justified on grounds of

public health protection and be proportionate in relation to the objective of such protection, in

compliance with the Treaty rules, particularly those concerning the free movement of goods

and competition.

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Article 168

Documentation accompanying supplied medicinal products

For all supplies of medicinal products to a person authorised or entitled to supply medicinal

products to the public in the Member State concerned, the authorised wholesaler must enclose

a document that makes it possible to ascertain the following:

(a) the date of the supply;

(b) the name and pharmaceutical form of the medicinal product;

(d) the name and address of the supplier of the medicinal product and consignee;

(e) the batch number of the medicinal products at least for products bearing the safety

features referred to in Article 67.

Member States shall take all appropriate measures to ensure that persons authorised or entitled

to supply medicinal products to the public are able to provide information that makes it

possible to trace the distribution path of every medicinal product.

Article 169

National requirements on wholesale distribution

The provisions of this Chapter shall not prevent the application of more stringent requirements laid

down by Member States in respect of the wholesale distribution of:

(a) narcotic or psychotropic substances;

(b) medicinal products derived from blood;

(d) radiopharmaceuticals.

Article 170

Wholesale distribution to third countries

In the case of wholesale distribution of medicinal products to third countries, Articles 162 and

166(1), point (dc), shall not apply.

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Where wholesale distributors supply medicinal products to persons in third countries, they shall

ensure that such supplies are only made to persons who are authorised or entitled to receive

medicinal products for wholesale distribution or supply to the public in accordance with the

applicable legal and administrative provisions of the third country concerned.

Article 168 shall apply to the supply of medicinal products to persons in third countries authorised

or entitled to supply medicinal products to the public.

Article 171

Brokering medicinal products

Persons brokering medicinal products shall ensure that the brokered medicinal products are

covered by a valid marketing authorisation granted in accordance with Union law.

Persons brokering medicinal products shall have a permanent address and contact details in

the Union, so as to ensure accurate identification, location, communication and supervision of

their activities by competent authorities of the Member States.

The requirements set out in Article 166(1), points (ef) to (kj), shall apply mutatis mutandis to

the brokering of medicinal products.

Persons may only broker medicinal products if they are registered with the competent

authority of the Member State where they have their permanent address referred to in

paragraph 1, second subparagraph. Those persons shall submit, by electronic means, at least,

their name, corporate name and permanent address to the competent authority in order to

of any changes thereof without undue delay.

Member States may provide for the possiblity of submission of the information referred

to in the first subparagraph in paper format.

The competent authority of the Member State shall enter the information referred to in the

first subparagraph in a register that shall be publicly available.

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The principles referred to in Article 160 shall include specific provisions for brokering.

Inspections referred to in Article 188 shall be carried out under the responsibility of the

Member State where the person brokering medicinal products is registered.

If a person brokering medicinal products does not comply with the requirements set out in this

Article, the competent authority of the Member State may decide to remove that person from

the register referred to in paragraph 2. In such event, the competent authority of the Member

State shall notify that person thereof.

Section 2

Sale at a distance to the public

Article 172

General requirements for sale at distance

Without prejudice to national legislation prohibiting the offer for sale at a distance of

prescription medicinal products to the public by means of information society services,

Member States shall ensure that medicinal products are offered for sale at a distance to the

public by means of services as defined in Directive (EU) 2015/1535 of the European

Parliament and of the Council45 laying down a procedure for the provision of information in

the field of technical regulations and of rules on Information Society services under the

following conditions:

(a) the natural or legal person offering the medicinal products is authorised or entitled to

supply medicinal products to the public, also at a distance, in accordance with national

legislation of the Member State in which that person is established;

(b) the person referred to in point (a) has notified the Member State in which that person is

established of at least the following information:

Directive (EU) 2015/1535 of the European Parliament and of the Council of 9 September 2015 laying
down a procedure for the provision of information in the field of technical regulations and of rules on
Information Society services (OJ L 241, 17.9.2015, p. 1).

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(i)

name or corporate name and permanent address of the place of activity from

where those medicinal products are supplied;

(ii) the starting date of the activity of offering medicinal products for sale at a distance

to the public by means of information society services;

(iii) the address of the website used for that purpose and all relevant information

necessary to identify that website;

(iv) if applicable, the prescription status in accordance with Chapter IV of the

medicinal products offered for sale at a distance to the public by means of

information society services.

Where appropriate, that information shall be updated;

destination in accordance with Article 5(1);

(d) without prejudice to the information requirements set out in Directive 2000/31/EC of

the European Parliament and of the Council46, the website offering the medicinal

products contains at least:

(i)

the contact details of the competent authority of the Member State or the authority

notified pursuant to point (b);

(ii) a hyperlink to the website referred to in Article 174 of the Member State of

establishment;

(iii) the common logo referred to in Article 173 clearly displayed on every page of the

website that relates to the offer for sale at a distance to the public of medicinal

products. The common logo shall contain a hyperlink to the entry of the person in

the list referred to in Article 174(1), point (c).

Member States may impose conditions, justified on grounds of public health protection, for

the retail supply on their territory of medicinal products for sale at a distance to the public by

means of information society services.

Directive 2000/31/EC of the European Parliament and of the Council of 8 June 2000 on certain legal
aspects of information society services, in particular electronic commerce, in the Internal Market
(Directive on electronic commerce (OJ L 178, 17.7.2000, p. 1).

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Without prejudice to Directive 2000/31/EC and the requirements set out in this Section,

Member States shall take the necessary measures to ensure that other persons than those

referred to in paragraph 1 that offer medicinal products for sale at a distance to the public by

means of information society services and that operate on their territory are subject to

effective, proportionate and dissuasive penalties.

Article 173

Requirements for common logo

A common logo shall be established that is recognisable throughout the Union, while enabling

the identification of the Member State where the person offering medicinal products for sale

at a distance to the public is established. That logo shall be clearly displayed on websites

offering medicinal products for sale at a distance to the public in accordance with Article

172(1), point (d).

In order to harmonise the functioning of the common logo, the Commission shall adopt

implementing acts regarding:

(a) the technical, electronic and cryptographic requirements for verification of the

authenticity of the common logo;

(b) the design of the common logo.

Those implementing acts shall, where necessary, be amended to take account of technical and

scientific progress. Those implementing acts shall be adopted in accordance with the

procedure referred to in Article 214(2).

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Article 174

Information about the supply at distance to the public

Each Member State shall set up a website providing at least the following:

(a) information on the national legislation applicable to the offering of medicinal products

for sale at a distance to the public by means of information society services, including

information on the fact that there may be differences between Member States regarding

classification of medicinal products and the conditions for their supply;

(b) information on the purpose of the common logo;

means of information society services in accordance with Article 172 as well as their

website addresses;

(d) background information on the risks related to medicinal products supplied illegally to

the public by means of information society services.

This website shall contain a hyperlink to the website referred to in paragraph 2.

The Agency shall set up a website providing the information referred to in paragraph 1, first

subparagraph, points (b) and (d), information on the Union law applicable to falsified

medicinal products as well as hyperlinks to the websites of the Member States referred to in

paragraph 1. The Agency’s website shall explicitly mention that the Member States’ websites

contain information on persons authorised or entitled to supply medicinal products by sales at

a distance in the Member State concerned.

The Commission shall, in cooperation with the competent authorities, conduct or promote

information campaigns aimed at the general public on the dangers of falsified medicinal

products. Those campaigns shall raise consumer awareness of the risks related to medicinal

products supplied illegally by sales at a distance as well as of the functioning of the common

logo and the websites referred to in paragraphs 1 and 2.

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Chapter XIII

Advertising

Article 175

Definition of advertising of medicinal products

For the purposes of this Chapter, ‘advertising of medicinal products’ shall include any form of

door-to-door information, canvassing activity or inducement designed to promote the

prescription, supply, sale or consumption of medicinal products.

It shall include in particular:

(a) the advertising of medicinal products to the general public;

(b) advertising of medicinal products to persons qualified to prescribe, administer while

providing healthcare or supply them, referred to in this Chapter as healthcare

professionals;

prescribe medicinal products;

(d) the supply of samples of medicinal products free of charge;

(e) the provision of inducements to prescribe or supply medicinal products by the gift, offer

or promise of any benefit or bonus, whether in money or in kind, except when their

intrinsic value is minimal;

(f)

sponsorship of promotional meetings attended by healthcare professionals persons

qualified to prescribe or supply medicinal products;

(g) sponsorship of or any other form of financial contribution for scientific congresses

events, attendend by persons qualified to prescribe or supply medicinal products

healthcare professionals and in particular payment to the organising entity, of their

participants’ travelling and, accomodation and catering expenses in connection

therewith.

(h) advertising related to medicinal products, that does not refer to specific medicinal

products.

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The following are not covered by this Chapter:

(a) the labelling and package leaflets, which are subject to the provisions of Chapter VI;

(b) correspondence, possibly accompanied by material of a non-promotional nature, needed

to answer a specific question about a particular medicinal product, provided it does not

promote the prescription or consumption of the medicinal product;

pack changes, adverse-reaction warnings as part of general drug precautions, trade

catalogues and price lists, provided they include no product claims;

(d) information relating to human health or diseases, provided that there is no reference,

even indirect, to medicinal products.

Article 176

General provisions on advertising of medicinal products

Member States shall prohibit any advertising of a medicinal product in respect of which a

marketing authorisation has not been granted.

All parts of the advertising of a medicinal product must comply with the particulars listed in

the summary of product characteristics.

The advertising of a medicinal product:

(a) shall encourage the rational use of the medicinal product, by presenting it objectively

and without exaggerating its properties;

(b) shall be accurate, verifiable and not be misleading.

Any form of advertising that aims to highlight negatively another medicinal product shall be

prohibited. Advertising that suggests that a medicinal product is safer or more effective than

another medicinal product shall also be prohibited, unless comparison of quality, safety and

efficacy is supported objectively by the complete demonstrated and supported by the

summariesy of product characteristics.

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Article 177

Restrictions on advertising of medicinal products

Member States shall prohibit the advertising to the general public of medicinal products that:

(a) are available on medical prescription only, in accordance with Chapter IV;

(b) contain substances classified as psychotropic or narcotic within the meaning of

international conventions.

Medicinal products may be advertised to the general public where, by virtue of their

composition and purpose, they are intended and designed for use without the intervention of a

medical practitioner for diagnostic purposes or for the prescription or monitoring of treatment,

with the advice of the pharmacist, if necessary.

Member States shall be entitled to ban, on their territory:,

advertising to the general public of medicinal products the cost of which may be

reimbursed;

advertising related to medicinal products that does not refer to a specific medicinal

product.

The prohibition contained in paragraph 1 shall not apply to vaccination campaigns promoting

vaccinations carried out or by the industry and approved by the competent authorities of the

Member States.

The prohibition referred to in paragraph 1 shall apply without prejudice to Article 21 of

Directive 2010/13/EU.

Member States shall prohibit the direct distribution of medicinal products to the public by the

industry for promotional purposes.

Member States may suspend the advertising of a medicinal product in case of shortages

or risk of shortage of this medicinal product. The suspension shall be withdrawn as

soon as the shortage or risk of shortage ceases.

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Member States may apply stricter measures with regard to advertisment of medicinal

products to healthcare professionals qualified to administer medicinal products.

Article 178

Advertising to the general public

Without prejudice to Article 177, all advertising to the general public of a medicinal product

shall:

(a) be set out in such a way that it is clear that the message is an advertisement and that the

product is clearly identified as a medicinal product; and

(b) include the following minimum information:

(i)

the name of the medicinal product, as well as the common name if the medicinal

product contains only one active substance;

(ii) the information necessary for correct use of the medicinal product;

(iii) an express, legible invitation to read carefully the instructions on the package

leaflet or on the outer packaging, as the case may be.

Member States may decide that the advertising of a medicinal product to the general public

may, notwithstanding paragraph 1, include only the name of the medicinal product or its

active substance, or the trademark if it is intended solely as a reminder.

Article 179

Restrictions on advertising to the general public

The advertising of a medicinal product to the general public shall not contain any material

that:

(a) gives the impression that a medical consultation or surgical operation is unnecessary, in

particular by offering a diagnosis or by suggesting treatment by any means of

communicationby mail;

(b) suggests that the effects of taking the medicinal product are guaranteed, are

unaccompanied by adverse reactions or are better than, or equivalent to, those of

another treatment or medicinal product;

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(d) suggests that the health of the subject could be affected by not taking the medicinal

product;

(e) is directed exclusively or principally at children;

(f)

refers directly or indirectly to a recommendation by scientists, healthcare

professionals, healthcare facilities or persons who are neither of the foregoing but who,

because of their celebrity or professional activity, could encourage the consumption of

medicinal products;

(g) suggests that the medicinal product is a food, cosmetic or other consumer product;

(h) suggests that the safety or efficacy of the medicinal product is due to the fact that it is of

natural origin natural;

(i)

could, by a description or detailed representation of a case history, lead to erroneous

self-diagnosis;

(j)

refers, in improper, alarming or misleading terms, to claims of recovery;

(k) uses, in improper, alarming or misleading terms, pictorial representations of changes in

the human body caused by disease or injury, or of the action of a medicinal product on

the human body or parts thereof.

The prohibition set out in the paragraph 1, point (d), shall not apply to the promotion of

vaccination campaigns referred to in Article 177(4).

Article 180

Advertising to persons qualified to prescribe, administer or supply medicinal products healthcare

professionals

Any advertising of a medicinal product to persons qualified to prescribe, administer or supply

such products healthcare professionals shall include both of the following:

(a) essential information compatible with the summary of product characteristics;

(b) the supply prescription status of the medicinal product.;

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Member States may also require such advertising to include the selling price or indicative

price of the various presentations and the conditions for reimbursement by social security

bodies.

Member States may decide that the advertising of a medicinal product to persons qualified to

prescribe, administer or supply such products healthcare professionals may, notwithstanding

paragraph 1, include only the name of the medicinal product, or its international non-

proprietary name, where this exists, or the trademark, if it is intended solely as a reminder.

Article 181

Supporting documentation for advertising to persons qualified to prescribe, administer or supply

medicinal products healthcare professionals

Any documentation relating to a medicinal product that is transmitted as part of the promotion

of that medicinal product to persons qualified to prescribe, administer or supply it shall

include, as a minimum, the particulars listed in Article 180(1) and shall state the date on

which it was drawn up or last revised.

All the information contained in the documentation referred to in paragraph 1 shall be

accurate, up-to-date, verifiable and sufficiently complete to enable the recipient to form their

own opinion of the therapeutic value of the medicinal product concerned.

Quotations as well as tables and other illustrative matter taken from medical journals or other

scientific works for use in the documentation referred to in paragraph 1 shall be faithfully

reproduced and the precise sources indicated.

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Article 182

Obligations related to medical sales representatives

Medical sales representatives shall be given adequate training by their employer undertaking

that employs them and shall have sufficient scientific knowledge to be able to provide

information that is precise and as complete as possible about the medicinal products that they

promote. The information provided by medical sales representatives shall be in accordance

with Article 176.

During each visit, medical sales representatives shall give the persons visited, or have

available for them, summaries of the product characteristics of each medicinal product they

present together, if the legislation of the Member State so permits, with details of the price

and conditions for reimbursement referred to in Article 180(1), second subparagraph.

Medical sales representatives shall transmit to the scientific service referred to in Article

187(1) any information about the use of the medicinal products they advertise, with particular

reference to any adverse reactions reported to them by the persons they visit.

Article 183

Promotion of medicinal products

Where medicinal products are being promoted to persons qualified to prescribe or supply

them healthcare professionals, no gifts, pecuniary advantages or benefits in kind may be

supplied, offered or promised to such persons unless they are inexpensive and relevant to the

practice of medicine or pharmacy.

Where medicinal products are being promoted at promotional events, hHospitality at

sales promotion events shall always be strictly limited to their the main purpose of the event

and shall respect the principles laid down in paragraph 1. and The hospitality must not

be extended to persons other than persons qualified to prescribe or supply medicinal products

healthcare professionals.

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Persons qualified to prescribe or supply medicinal products Healthcare professionals shall

not solicit or accept any inducement prohibited under paragraph 1 or contrary to paragraph 2.

Existing measures or trade practices in Member States relating to prices, margins and

discounts shall not be affected by the rules set out in paragraphs 1, 2 and 3.

Article 184

Hospitality at scientific events

The provisions of Article 183(1) shall be respected when not prevent hospitality is being offered,

directly or indirectly, at events for purely professional and scientific purposes. Such hospitality is

justified only when indispensable for the fulfilment of shall always be strictly limited to the main

scientific objective of the event. It must not be extended to persons other than persons qualified to

prescribe or supply medicinal products healthcare professionals.

Article 185

Provision of samples of medicinal products free of charge

Free sSamples of medicinal products shall be provided free of charge on an exceptional basis

only to persons qualified to prescribe them and on the following conditions:

(a) the number of samples for each medicinal product each year on prescription shall be

limited;

(b) any supply of samples shall be in response to a written request, signed and dated, from

the persons qualified to prescribe or supply medicinal products;

control and accountability;

(d) each sample shall be no larger than the smallest presentation on the market;

(e) each sample shall be marked ‘free medical sample — not for sale’ or shall show some

other wording having the same meaning;

(f)

each sample shall be accompanied by a copy of the summary of product characteristics;

(g) no samples of medicinal products containing substances classified as psychotropic or

narcotic within the meaning of international conventions may be supplied.

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Member States may decide that oOn an exceptional basis, free samples of medicinal

products not subject to medical prescription may also be provided to persons qualified to

supply them, subject to the conditions of paragraph 1.

Member States may also place further restrictions on the distribution of samples of certain

medicinal products free of charge.

Article 186

Implementation of advertising provisions by the Member States

Member States shall ensure that there are adequate and effective methods to monitor the

advertising of medicinal products. Such methods, which may be based on a system of prior

vetting, shall in any event include legal provisions under which persons or organisations

regarded under national law as having a legitimate interest in prohibiting any advertisement

inconsistent with this Chapter, may take legal action against such advertisement, or bring such

advertisement before the competent authority of the Member State either to decide on

complaints or to initiate appropriate legal proceedings.

Under the legal provisions referred to in paragraph 1, Member States shall confer upon the

courts or competent authorities of the Member States powers enabling them, in cases where

they deem such measures to be necessary, taking into account all the interests involved, and in

particular the public interest:

(a) to order the cessation of, or to institute appropriate legal proceedings for an order for the

cessation of, misleading advertising; or

(b) if misleading advertising has not yet been published but publication is imminent, to

order the prohibition of, or to institute appropriate legal proceedings for an order for the

prohibition of, such publication.

Member States shall confer upon the courts or competent authorities of the Member States the

powers referred to in the first subparagraph, points (a) and (b), even without proof of actual

loss or damage or of intention or negligence on the part of the advertiser.

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Member States shall make provision for the measures referred to in paragraph 2 to be taken

under an accelerated procedure, either with interim effect or with definitive effect.

It shall be for each Member State to decide which of the two options set out in the first

subparagraph to select.

Member States may confer upon the courts or competent authorities of the Member States

powers enabling them, with a view to eliminating the continuing effects of misleading

advertising the cessation of which has been ordered by a final decision:

(a) to require publication of that decision in full or in part and in such form as they deem

adequate;

(b) to require in addition the publication of a corrective statement.

The paragraphs 1 to 4 shall not exclude the voluntary control of advertising of medicinal

products by self-regulatory bodies and recourse to such bodies, if proceedings before such

bodies are possible in addition to the judicial or administrative proceedings referred to in

paragraph 1.

Article 187

Implementation of advertising provisions by the marketing authorisation holder

The marketing authorisation holders shall establish, within their undertaking or not-for-profit

entities,organisation a scientific service in charge of information about the medicinal

products that they place on the market.

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The marketing authorisation holder shall:

(a) keep available for, or communicate to, the competent authorities of the Member States

or bodies responsible for monitoring advertising of medicinal products, a sample of all

advertisements emanating from its undertaking or not-for-profit entities together with a

statement indicating the persons to whom it is addressed, the method of dissemination

and the date of first dissemination;

(b) ensure that advertising of medicinal products by their undertaking or not-for-profit

entities conforms to the requirements of this Chapter;

entities have been adequately trained and fulfil the obligations imposed upon them by

Article 182, paragraphs 2 and 3;

(d) supply the competent authorities of the Member States or bodies responsible for

monitoring advertising of medicinal products with the information and assistance they

require to carry out their responsibilities;

(e) ensure that the decisions taken by the competent authorities of the Member States or

bodies responsible for monitoring advertising of medicinal products are immediately

and fully complied with.

The Member States shall not prohibit the co-promotion of a medicinal product by the

marketing authorisation holders and one or more companies nominated by them.

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Chapter XIV

Supervision and controls

Section 1

Supervision

Article 188

System of supervision and inspections

The competent authority of the Member State concerned shall, in cooperation with the

Agency and where relevant, other Member States, ensure compliance with the rules of this

Directive, namely including the principles of good manufacturing practice and good

distribution practices referred to in Articles 160 and 161.

For the purposes of the first subparagraph, the competent authority of the Member State shall

have in place a system of supervision that shall include the following measures:

(a) announced and, where appropriate, unannounced on-site inspections;

(b) remote inspections, conducted where justified;

(d) the effective follow-up of the measures referred to in points (a), (b) and (c).

The competent authorities of the Member State concerned, and the Agency shall exchange

information on the inspections referred to in paragraph 1, second subparagraph, points (a) and

(b), that are planned or that have been conducted and shall cooperate in the coordination of

such inspections.

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The competent authority of the Member State shall ensure that the measures referred to in

paragraph 1, second subparagraph, are carried out by the official representatives of the

competent authority of the Member State concerned:

(a) at an appropriate frequency based on risk, at the premises or on the activities of

manufacturers of medicinal products, located in the Union or in third countries,

including where appropriate at central or decentralised site(s), and at the premises or on

the activities of wholesale distributors of medicinal products located in the Union;

(b) at an appropriate frequency based on a risk assessment, at the premises or on the

activities of the manufacturers of active substances located in the Union or in third

countries and at the premises or on the activities of importers, or distributors of active

substances, located in the Union.

To implement determine the appropriate frequency based on a risk assessment referred to in

paragraph 3, point (b), the competent authority of the Member State may:

(a) rely on inspection reports from trusted non-Union regulatory authorities;

(b) take into account whether the manufacturer of active substance is located in a third

country included in the list referred to in Article 159(2).

Where the competent authority of the Member State considers it necessary, in particular

including where there are grounds for suspecting non-compliance with the rules of this

Directive, including with the principles of good manufacturing practice and good distribution

practices, referred to in Articles 160 and 161, it may have its official representatives carry out

the measures referred to in paragraph 1, second subparagraph at the premises or on the

activities of:

(a) applicants manufacturers or importers of medicinal products applying for a

manufacturing import authorisation or wholesale distributors applying for a wholesale

distribution authorisation of medicinal products;

(b) applicants manufacturers of active substance applying for a registration of

manufacturing, import and distribution of active substances or manufacturing sites

applying for a registration as decentralised sites;

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(ba) decentralised sites subject to request for a registration and registered decentralised

sites;

(d) without prejudice to paragraph 3, manufacturers, wholesale distributors of

medicinal products, manufacturers and distributors of medicinal products or active

substances located in the Union or in third countries and importers of medicinal

products or active substances located in the Union;

(e) manufacturers of excipients, functional excipients, starting materials or intermediate

products located in its territory or in a third country;

(f)

importers of excipients, functional excipients, starting materials or intermediate

products located in its territory;

(g) persons brokering medicinal products located in its territory.;

(h) third parties, contracted by the marketing authorisation holder or a marketing

authorisation applicant for the performance of certain of its tasks or the

preparation of evidence or data submitted in accordance with Annex II.

The measures referred to in paragraph 1, second subparagraph, may also be carried out at the

request of a competent authority of a Member State, the Commission or the Agency in the

Union or in third countries or, where appropriate, by asking an Official Medicines Control

Laboratory or a laboratory that Member State has designated for that purpose to carry out tests

on samples.

Each Member State shall ensure that official representatives of its competent authorities are

empowered and required to carry out one or more of the following activities:

(a) inspect the manufacturing or commercial establishments of manufacturers of medicinal

products, of active substances or of excipients, and any laboratories employed by the

manufacturing authorisation holder to carry out verifications and controls pursuant to

Article 8;

(aa) examine any documents and records to verify compliance with the particulars of

this Directive, and obtain evidence, such as copies of documents, photographs or

videos.

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(b) take samples during an inspection or request samples as part of the measures referred to

in paragraph 1, second subparagraph, including any required essential testing material

or reagent with a view to independent tests being carried out by an Official Medicines

Control Laboratory or a laboratory that a Member States has designated for that

purpose;

the marketing authorisation holder or any undertaking employed by the marketing

authorisation holder to perform the activities described in Chapter IX.

Inspections referred to in paragraph 1, second subparagraph, points (a) and (b), shall be

carried out in accordance with the principles referred to in Article 190.

After every inspection carried out in accordance with paragraphs 3 and 5, the competent

authority of the Member State concerned shall issue a report on the compliance of the

manufacturing activities entity inspected with the requirements of the conduct of activities

including the compliance of the activities with the good manufacturing practice and good

distribution practices referred to in Articles 160 and 161, as applicable.

10. The competent authority of the Member State that had its official representatives carry out

inspections in accordance with paragraphs 3 and 5, shall share its draft initial report with the

inspected entity.

11. Before adopting the report, the competent authority of the Member State shall give the

inspected entity the opportunity to submit comments.

12. Without prejudice to any arrangements that may have been concluded between the Union and

third countries, a Member State, the Commission or the Agency may require a manufacturer

of a medicinal product or of an active substance established in a third country to submit to an

inspection as referred to in this Article.

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13. Within 90 days of the conclusionafter conducting of an inspection carried out in accordace

with paragraphs 3 and 5 the competent authority of the Member State concerned shall issue to

the inspected entity a certificate of compliance of good manufacturing practice (GMP) or

good distribution practices (GDP) if the outcome of that inspection shows that the inspected

entity complies with the principles of good manufacturing practice or good distribution

practices referred to in Articles 160 and 161.

14. If the outcome of the inspection carried out in accordance with paragraph 3, 4 and 3 and 5

shows that the inspected entity does not comply with the principles of good manufacturing

practice or good distribution practices as referred to in Articles 160 and 161, the competent

authority of the Member State concerned shall issue a statement of non-compliance, as

appropriate and shall revoke the certificate of compliance with good manufacturing

practice or good distribution practice fully or partially, as appropriate.

15. The competent authority of the Member State shall enter the certificates of good

manufacturing practice or good distribution practices in the relevant Union database managed

by the Agency on behalf of the Union. Pursuant to Article 157, paragraph 6 and 7 the

competent authority of the Member States shall also enter information in that database

regarding the registration of importers, manufacturers and distributors of active substances

and decentralised sites performing decentralised manufacturing activities, referred to in

Article 148, paragraph 3, letter point b and paragraph 11. including their respective

database link to the manufacturing authorisation of the central site.

16. If the outcome of the inspection carried out in accordance with paragraph 3 and 5 is that the

inspected entity does not comply with the legal requirements or the principles of good

manufacturing practice or good distribution practices as referred to in Articles 160 and 161

the information shall be entered in the Union database as referred to in paragraph 15, as

appropriate.

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17. If the outcome of the activity carried out in accordance with paragraph 7, point (c), is that the

marketing authorisation holder does not comply with the pharmacovigilance system as

described in the pharmacovigilance system master file and with Chapter IX, the competent

authority of the Member State concerned shall bring the deficiencies to the attention of the

marketing authorisation holder and give the marketing authorisation holder the opportunity to

submit comments.

In such case the Member State concerned shall inform the other Member States, the Agency

and the Commission accordingly.

Where appropriate, the Member State concerned shall take the necessary measures to ensure

that a marketing authorisation holder is subject to effective, proportionate and dissuasive

penalties as laid down in Article 206.

Article 189

Cooperation on inspections

Upon request by one or more competent authorities of the Member States, inspections

referred to in Article 188, paragraphs 3 and 5, may be carried out by official representatives

from more than one Member State, together with the inspectors of the Agency if specifically

requested by the aforementioned competent authority in accordance with Article 52(12),

point (a) of [revised Regulation (EC) 726/2004] (‘the joint inspection’).

The competent authority of the Member State receiving a request for a joint inspection, shall

make all reasonable efforts, taking into account their available resources, to accept such a

request, and coordinate and support that joint inspection, where:

(a) it is demonstrated, or there are reasonable ground for suspecting, that the activities

carried out on the territory of the Member State receiving the request pose a risk to the

safety and quality of the medicinal product in the Member State of the competent

authority requesting the joint inspection and the competent authorities of the

concerned Member States agree that an inspection is needed;

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(b) competent authorities of the Member State requesting the joint inspection require

specialist technical expertise available in the Member State receiving the joint

inspection request;

other reasonable grounds such as training of inspectors, sharing of good practice, for for

conducting a joint inspection.

The competent authorities participating in a joint inspection shall conclude an agreement prior

to the inspection that defines at least the following:

(a) the scope and objective of the joint inspection;

(b) the roles of the participating inspectors during and following the inspection, including

the designation of an authority leading the inspection.; Where the joint inspection is

conducted on the territory of one of the Member States, the competent authority of

that Member State shall act as the leading authority for the joint inspection, unless

otherwise agreed between the Member States;

The competent authorities participating in the joint inspection shall commit themselves in that

agreement to jointly accept the results of the inspection.

Where the joint inspection is conducted in one of the Member States, the competent authority

leading the joint inspection of that Member State shall ensure that the joint inspection is

carried out in accordance with the national legislation of the Member State in which the joint

inspection takes place.

Member States may set up joint inspection programmes to facilitate routine joint inspections.

Member States may operate such programmes under a agreement as referred to in paragraphs

2 and 3.

A competent authority of a Member State may request another competent authority to take

over one of its inspections referred to in Article 188, paragraphs 3 and 5.

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The other competent authority of the Member State shall communicate to the requesting

competent authority whether it accepts the request to conduct the inspection within 10 days.

Where it accepts, it shall be responsible as the competent authority to carry out the inspections

pursuant to this Section.

For the purposes of paragraph 6, and when the request is agreed, the requesting competent

authority shall, in a timely manner, submit the relevant information necessary to conduct the

inspection to the competent authority of the Member State that accepted the request.

Article 190

Principles applicable to supervision and Iinspections guidelines

The Commission may shall adopt implementing delegated acts to lay down the principles

applicable to:

(a) the system of supervision referred to in Article 188(1);

(b) the joint inspections referred to in Article 189(1);

system of supervision between the Member States and the Agency referred to in

Article 188(2); and

(d) trusted non-Union regulatory authorities referred to in Article 188(4)(a).;

(e) the exchange of information and cooperation as regards decentralised

manufacturing between the competent authorities in charge of the supervision of

the central site and decentralised sites and of the marketing authorisation referred

to in Article 148.

The implementing delegated acts referred to in the first subparagraph shall be adopted in

accordance with the procedure referred to in Article 215 214(2).

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Member States shall, in cooperation with the Agency, establish the form and content of the

manufacturing authorisation referred to in Article 142(1) and of the wholesale distribution

authorisation referred to in Article 163(1), of the report referred to in Article 188 (9), of the

certificates of good manufacturing practice and of the certificates of compliance with good

distribution practices referred to in Article 188(13) and the statement of non-compliance

referred to in Article 188(14).

Section 2

Controls

Article 191

Controls on medicinal products

Member States shall take all appropriate measures to ensure that the marketing authorisation holder

for a medicinal product and, where appropriate, the manufacturing authorisation holder, furnish

proof of the controls carried out on the medicinal product or the ingredients and of the controls

carried out at an intermediate stage of the manufacturing process, in accordance with the methods

laid down in Annex I.

Article 192

Submission of control reports for immunological medicinal products and of medicinal products

derived from human blood or plasma

For the purpose of implementing Article 191, Member States may require manufacturers of

immunological products and of medicinal products derived from human blood or plasma to

submit to a competent authority of the Member States copies of all the control reports signed by the

qualified person in accordance with Article 153.

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Article 193

Batch control of specific medicinal product by Member States

Where it considers it necessary in the interests of public health, a Member State may require

the marketing authorisation holder of:

(a) live vaccines,

(b) immunological medicinal products used in the primary immunisation of infants or of

other groups at risk,

(d) new immunological medicinal products or immunological medicinal products

manufactured using new or altered kinds of technology or new for a particular

manufacturer, during a transitional period normally specified in the marketing

authorisation,

to submit samples from each batch of the bulk or the medicinal product and from the bulk if

required for examination by an Official Medicines Control Laboratory or a laboratory that a

Member State has designated for that purpose before release on to the market unless the

competent authority of another Member State has previously examined the batch in question

and declared it to be in conformity with the approved specifications. In such a case the

declaration of conformity issued by another Member States shall be directly recognised.

The marketing authorisation holder, in consultation with the Official Medicines Control

Laboratory, shall make reasonable efforts to submit samples for examination at the

beginning of their own controls.

Member States shall ensure that any such examination is completed within 30 days of the

receipt both of the samples and documentation of the controls carried out by the

marketing authorisation holder in accordance with Article 191. This period of time shall

be extended to 60 days if necessary to complete the examination.

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Where, in the interests of public health, the laws of a Member State so provide, the competent

authorities of the Member State may require the marketing authorisation holder for medicinal

products derived from human blood or human plasma to submit samples from each batch of

the bulk or the medicinal product and from the bulk if required, for testing by an Official

Medicines Control Laboratory or a laboratory that a Member State has designated for that

purpose before being released into on the marketfree circulation, unless the competent

authorities of another Member State have previously examined the batch in question and

declared it to be in conformity with the approved specifications. In such a case the

declaration of conformity issued by another Member State shall be recognised.

The marketing authorisation holder, in consultation with the Official Medicines Control

Laboratory, shall make reasonable efforts to submit samples for examination at the

beginning of their own controls. Member States shall ensure that any such examination is

completed within 60 30 days of the receipt both of the samples and documentation of the

controls carried out by the marketing authorisation holder in accordance with Article

191. This period of time shall be extended to 60 days if necessary to complete the

examination.

Article 194

Processes for the preparation of medicinal products derived from human blood or human plasma

Member States shall take all necessary measures to ensure that the manufacturing and

purifying processes used in the preparation of medicinal products derived from human blood

or human plasma are properly validated, attain batch-to-batch consistency and guarantee,

insofar as the state of technology permits, the absence of specific viral contamination.

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To this end manufacturers shall notify the competent authorities of the Member States of the

method used to reduce or eliminate pathogenic viruses liable to be transmitted by medicinal

products derived from human blood or human plasma. The competent authority of the

Member State may submit samples of the bulk or the medicinal product and from the bulk if

required, for testing by a State laboratory or a laboratory designated for that purpose, either

during the examination of the application pursuant to Article 29, or after a marketing

authorisation has been granted.

Chapter XV

Restrictions of marketing and manufacturing authorisations

Article 195

Suspending, revoking or varying the terms of marketing authorisations

The competent authorities of the Member States or, in the case of centralised marketing

authorisation, the Commission shall suspend, revoke or vary a marketing authorisation if the

view is taken that the medicinal product is harmful or that it lacks therapeutic efficacy, or that

the benefit-risk balance is not favourable, or that its qualitative and quantitative composition

is not as declared. Therapeutic efficacy shall be considered to be lacking when it is concluded

that therapeutic results cannot be obtained from the medicinal product.

The competent authorities of the Member States or, in the case of centralised marketing

authorisation, the Commission may suspend, revoke or vary a marketing authorisation if a

serious risk to the environment or public health has been identified and not sufficiently

addressed by the marketing authorisation holder

A marketing authorisation may also be suspended, revoked or varied where the particulars

supporting the application as provided for in Articles 6, 9 to 14 or Annexes I to V are

incorrect or have not been amended in accordance with Article 90, or where any conditions

referred to in Articles 44, 45 and 87 have not been fulfilled or where the controls referred to in

Article 191 have not been carried out.

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Paragraph 2 3 also applies in cases where the manufacture of the medicinal product is not

carried out in compliance with the particulars provided pursuant to Annex I, or where controls

are not carried out in compliance with the control methods described pursuant to Annex I.

The competent authorities of the Member State or, in the case of centralised marketing

authorisation, the Commission shall may suspend or revoke the marketing authorisation for a

category of preparations or all preparations where any one of the requirements laid down in

Article 143 is no longer met.

Article 196

Prohibition of supply or withdrawal of a medicinal product from the market

Without prejudice to the measures provided for in Article 195, the competent authorities of

the Member States and, in the case of centralised marketing authorisation, the Commission

shall take all appropriate steps to ensure that the supply of the medicinal product is prohibited

and the medicinal product withdrawn from the market, if the view is taken that:

(a) the medicinal product is harmful;

(b) it lacks therapeutic efficacy;

(d) its qualitative and quantitative composition is not as declared;

(e) the controls on the medicinal product or on the ingredients and the controls at an

intermediate stage of the manufacturing process have not been carried out or if some

other requirement or obligation relating to the grant of the manufacturing authorisation

has not been fulfilled; or

(f)

a serious risk to the environment or to public health via the environment has been

identified and not sufficiently addressed by the marketing authorisation holder.

The competent authority of the Member State or, in the case of centralised marketing

authorisation, the Commission may limit the prohibition to supply the product, or its

withdrawal from the market, to those batches that are the subject of dispute.

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The competent authority of the Member State or, in the case of centralised marketing

authorisation, the Commission may, for a medicinal product for which the supply has been

prohibited or that has been withdrawn from the market in accordance with paragraphs 1 and 2,

in exceptional circumstances during a transitional period allow the supply of the medicinal

product to patients who are already being treated with the medicinal product.

Article 197

Suspected falsified medicinal products and medicinal products with suspected quality defects

Member States shall have a system in place that aims at preventing medicinal products that

are suspected to present a danger to health from reaching the patient.

The system referred to in paragraph 1 shall cover the receipt and handling of notifications of

suspected falsified medicinal products as well as of medicinal products with suspected quality

defects. The system shall also cover recalls of medicinal products by marketing authorisation

holders or withdrawals of medicinal products from the market ordered by competent

authorities of the Member States or, in the case of centralised marketing authorisation, the

Commission from all relevant actors in the supply chain both during and outside normal

working hours. The system shall also make it possible to recall, where necessary with the

assistance of health professionals, medicinal products from patients who received such

products.

If the medicinal product in question is suspected of presenting a serious risk to public health,

the competent authority of the Member State in which that product was first identified shall,

without undue delay, transmit a rapid alert notification to all Member States and all actors in

the supply chain in that Member State. In the event of such medicinal products being deemed

to have reached patients, urgent public announcements shall be issued within 24 hours in

order to recall those medicinal products from the patients. Those announcements shall contain

sufficient information on the suspected quality defect or falsification and the risks involved.

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Article 198

Suspending or revoking manufacturing authorisation

In addition to the measures specified in Article 196, the competent authority of the Member State

may suspend manufacture or imports of medicinal products coming from third countries, or suspend

or revoke the manufacturing authorisation for a category of preparations or all preparations where

Articles 144, 147, 153 and 191 are not complied with.

Article 199

Refusal, suspension or revocation within the limits of the Directive

A marketing authorisation to market of a medicinal product shall not be refused, suspended

or revoked except on the grounds set out in this Directive.

No decision concerning suspension of manufacture or of importation of medicinal products

coming from third countries, prohibition of supply or withdrawal from the market of a

medicinal product may be taken except on the grounds set out in Articles 195(5) and 196..

Chapter XVI

General provisions

Article 200

Competent authorities of the Member States

Member States shall designate the competent authorities to carry out tasks under this

Directive.

Member States shall ensure that adequate financial resources are available to provide the staff

and other resources necessary for the competent authorities to carry out the activities required

by this Directive and [revised Regulation (EC) No 726/2004].

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The competent authorities of the Member States shall cooperate with each other and with the

Agency and the Commission in the performance of their tasks under this Directive and

[revised Regulation (EC) No 726/2004] to ensure proper application and due enforcement.

The competent authorities of the Member States shall transmit communicate to each other all

necessary appropriate information within a reasonable timeframe.

The competent authority of the Member State may process personal health data from sources

other than clinical studies to support their public health tasks and, in particular, the evaluation

and monitoring to medicinal products, for the purpose of improving the robustness of the

scientific assessment or verifying claims of the applicant or marketing authorisation holder.

Processing of personal data under this Directive shall be subject to Regulations (EU)

2016/679 and (EU) 2018/1725, as applicable.

Article 201

Cooperation with other authorities

Member States, in applying this Directive, shall ensure that when questions arise with regard

to the regulatory status of a medicinal product, in relation to their link to substances of human

origin as referred to in Regulation (EU) No [SoHO Regulation], the competent authorities of

the Member States shall consult the relevant authorities established under that Regulation.

1a. In all cases where questions arise as to the regulatory status of a product which are

either under development or products already on the market in the EU or an EU

Member State and which may fall under the definition of an medicinal product that

cannot be resolved at national level, or where different Member States have a different

view with regard to the regulatory status of the same product, the national competent

authorities may consult the regulatory status advisory committee provided for in article

201a for an opinion on the regulatory status of the product. The regulatory status

advisory committee shall issue its opinion within 90 days following the request.

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Member States, in applying this Directive, shall take the necessary measures to ensure

cooperation between competent authorities for medicinal products and customs authorities.

Article 201a

Determination of regulatory status

A regulatory status advisory committee is hereby established.

The Committee shall be responsible for the examination and drawing up a

recommendation where questions arise as to the regulatory status of a substance or

product upon request of a national competent authority in accordance with Article 201

(1a).

The Committee shall be responsible for the examination of questions relating to the

regulatory status of a substance or product upon request of a national competent

authority in accordance with Article 201 (1a) and the adoption of recommendations

relating to the regulatory status of a substance or product.

The committee shall be composed of representatives of the Agency and representatives

appointed by Member States.

Each Member State and the Agency shall appoint to this committee one member and

one alternate with expertise in the qualification and classification of substance or

products under this Directive, [new Regulation] and other related Union legislation,

such as and not limited to Regulation (EU) 2017/745, Regulation (EU) 2017/746 and

Regulation (EU) 2024/1938. The term for each member shall be three years, which may

be renewed.

The alternates shall represent and vote for the members in their absence.

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The Committee shall use its best endeavors to reach consensus. If such consensus cannot

be reached, the Committee shall decide by a majority of its members. Members with

diverging positions may request that their positions and the grounds on which they are

based be recorded in the Committee’s position.

The Committee shall be chaired by a representative of the Commission. The chair shall

not take part in votes of the Committee.

The Committee shall consult, where appropriate, relevant advisory or regulatory bodies

established in other Union legal acts in related fields. The Committee may also invite, on

a case-by-case basis, experts and other third parties to attend meetings or provide

written contributions.

The Committee shall establish its rules of rules of procedure, which shall, in particular,

lay down procedures for the following:

(a) the adoption of recommendations;

(b) delegation of tasks to reporting or co-reporting members.

The Commission shall publish summaries of the recommendations issued in accordance

with paragraph 2, after deletion of all information of a commercially confidential

nature.

Article 202

Member States exchange of information of manufacturing or wholesale distribution authorisations

of medicinal products

Member States shall take all appropriate measures to ensure that the competent authorities of

the Member States concerned communicate to each other such information as is appropriate to

guarantee that the requirements placed on the authorisations referred to in Articles 142 and

163, on the certificates referred to in Article 188(13) or on the marketing authorisations are

fulfilled.

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Upon reasoned request, Member States shall send electronically the report referred to in with

Article 188 to the competent authorities of another Member State or to the Agency.

The conclusions reached in accordance with Articles 188(13) or 188(14) shall be valid

throughout the Union.

However, in exceptional cases, if a Member State is unable, for reasons relating to public

health, to accept the conclusions reached following an inspection under Article 188(1), that

Member State shall without undue delay inform the Commission and the Agency. The

Agency shall inform the Member States concerned.

When the Commission is informed of these divergences of opinion, it may, after consulting

the Member States concerned, ask the inspector who performed the original inspection to

perform a new inspection; the inspector may be accompanied by two other inspectors from

Member States that are not parties to the disagreement.

Article 203

Information on prohibition of supply or other action on a marketing authorisation

Each Member State shall take all the appropriate measures to ensure that decisions granting

marketing authorisation, refusing or revoking a marketing authorisation, cancelling

withdrawing a decision refusing or revoking a marketing authorisation, prohibiting supply, or

withdrawing a product from the market, together with the reasons on which such decisions are

based, are brought to the attention of the Agency without undue delay.

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In addition to the notification made pursuant to Article 116 of [revised Regulation (EC) No

726/2004], the marketing authorisation holder shall declare without undue delay if such

notified action is based on any of the grounds set out in Articles 195 or 196(1).

The marketing authorisation holder shall notify the national competent authority

without undue delay of any action they take to suspend the marketing of a medicinal

product, to withdraw a medicinal product from the market, to request the withdrawal of

a marketing authorisation or not to apply for the renewal of a marketing authorisation,

together with the reasons for such action. The marketing authorisation holder shall

declare if such notified action is based on any of the grounds set out in Articles 195 or

196(1) and specify the grounds for such action.

2a. The marketing authorisation holder shall make the notification electronically and in the

formats made available by the Agency. The Agency shall consult the Member States

when drawing up the formats.

The marketing authorisation holder shall also make the notification pursuant to paragraph 2 in

cases where the action is taken in a third country and where such action is based on any of the

grounds set out Articles 195 or 196(1).

The marketing authorisation holder shall furthermore notify the Agency where the action

referred to in paragraphs 2 or 3 is based on any of the grounds referred to in Articles 195 or

196(1).

The Agency shall forward notifications received in accordance with paragraph 4 to all

Member States without undue delay.

Member States shall ensure that appropriate information about action taken pursuant to

paragraphs 1 and 2 that may affect the protection of public health in third countries is without

undue delay brought to the attention of the World Health Organization, with a copy to the

Agency.

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Each year, the Agency shall make public a list of the medicinal products for which marketing

authorisations have been refused, revoked or suspended in the Union, whose supply has been

prohibited or that have been withdrawn from the market, including the reasons for such

action.

Article 204

Notification of decisions related to marketing authorisations

Every decision referred to in this Directive that is taken by the competent authority of a

Member State shall state in detail the reasons on which it is based.

Such decision shall be notified to the party concerned, together with information as to the

redress available to them under the laws in force and of the time limit allowed for access to

such redress.

Decisions to grant or revoke a marketing authorisation shall be made publicly available.

Article 205

Authorisation of a medicinal product on public health grounds

In the absence of a marketing authorisation or of a pending application for a medicinal

product authorised in another Member State in accordance with Chapter III, a Member State

may for justified public health reasons, such as the need to ensure access, availability or

security of supply, authorise the placing on the market of the said medicinal product.

When a Member State avails itself of this possibility, it shall adopt the necessary measures in

order to ensure that the requirements of this Directive are complied with, in particular those

referred to in Chapters IV, VI, IX, XIII and XIV, and Article 206. Member States may decide

that Article 74, paragraphs 1 to 3, shall not apply to medicinal products authorised under

paragraph 1.

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Before granting such a marketing authorisation, a Member State:

(a) shall notify the marketing authorisation holder, in the Member State in which the

medicinal product concerned is authorised, of the proposal to grant a marketing

authorisation under this Article in respect of the medicinal product concerned;

(b) may request the competent authority in that Member State to submit copies of the

assessment report referred to in Article 43(5) and of the marketing authorisation in force

in respect of the medicinal product concerned. If so requested, the competent authority

in that Member State shall supply, within 30 days of receipt of the request, a copy of the

assessment report and the marketing authorisation in respect of the medicinal product

concerned.

The Commission shall set up a publicly available register of medicinal products authorised

under paragraph 1. Member States shall notify the Commission if any medicinal product is

authorised, or ceases to be authorised, under paragraph 1, including the name or corporate

name and permanent address of the marketing authorisation holder. The Commission shall

amend the register of medicinal products accordingly and make this register available on their

website.

Article 206

Penalties

Member States shall lay down the rules on penalties applicable to infringements of national

provisions adopted pursuant to this Directive and shall take all measures necessary to ensure

that they are implemented. The penalties must be effective, proportionate and dissuasive.

Member States shall, without delay, notify the Commission of those rules and of those

measures and shall notify without delay of any subsequent amendment affecting them.

Those penalties shall not be inferior to those applicable to infringements of national law of

similar nature and importance.

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The rules referred to in paragraph 1, first subparagraph, shall address, inter alia, the following:

(a) the manufacturing, distribution, brokering, import and export of falsified medicinal

products, as well as sale at distance of falsified medicinal products to the public;

(aa) non-compliance with the provisions laid down in this Directive on manufacturing,

distribution, brokering, import and export of medicinal products as well as sale at

distance of medicinal products to the public;

(b) non-compliance with the provisions laid down in this Directive on manufacturing,

distribution, import and export of active substances;

(d) non-compliance with the provisions laid down in this Directive on pharmacovigilance;

(e) non-compliance with the provisions laid down in this Directive on advertising.

Where relevant, the penalties shall take into account the risk to public health presented by the

falsification of medicinal products.

Article 207

Collection of unused or expired medicinal products

Member States shall ensure that appropriate collection systems are in place for medicinal products

that are unused or have expired.

Article 207a

Redispensing to the public of unused medicinal products

A Mmedicinal products collected in accordance with Article 207 shall not be re-

dispensed to the publicpatients.

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By way of derogation from paragraph 1, Member States may allow specific unused

medicinal products subject to prescription and bearing the safety features referred to in

Article 67 that, after having been supplied dispensed to the patients, have been collected

by a pharmacy to be re-dispensed to their patients if all of the following conditions are

met:

(a) the medicinal product is re-dispensed by the same pharmacy that initially supplied

dispensed it to the public and the pharmacy is authorised by a the competent

authority Member State to re-dispense medicinal products; and

(b) the collection of the unused medicinal product is not prejudicial to the patient to

whom it was initially dispensed;

(c) the collected medicinal product has not been already the subject of re-

dispensation;

(d) the medicinal product was initially dispensed with a view of being potentially re-

dispensed and necessary safeguards were applied by the dispensing pharmacy to

ensure that this medicinal product is not tampered with and its storage and

transport conditions will be respected;

(eb) the re-dispendsed medicinal product is to intended for use of an individual named

patient;

(fc) the patient referred to in point (b) has explicitly given their written consent to be

supplied with a re-dispensed medicinal products after being infomed by the

pharmacy of the use of a re-dispensed medicinal product and the rules concerning

re-dispensing laid out in applicable national laws in accordance with this Article.

Member States shall ensure that before a pharmacy redispenses medicinal products to

their patients in accordance with paragraph 2, such pharmacy:

(a) verifies that the medicinal product concerned is not a falsified medicinal product,

(b) verifies that the expiration date of the medicinal product has not been exceeded

and the package it has been stored and transported under the appropriate

conditions,

(c) records the name and the batch number of the medicinal product, the person from

whom the medicinal product has been collected, and the receiving patient for the

purpose of recall, investigations and supervision.

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Member States may set list of categories of medicinal products which are allowed to

returned and additional restrictive conditions under which medicinal products may be

re-dispensed to the patients in their territory.

4a. Member States shall ensure that the collection and re-dispensing of medicinal products

will not be used for obtaining economic gains and penetration of the re-dispensed

medicines to the supply chain.

Member States shall lay down rules on liability for potential damages resulting from the

use of the medicinal products that have been re-dispensed when such damages are a

consequence of a failure to ensure appropriate storage or transport conditions between

the initially dispensing and returning to the pharmacy, or a failure to ensure that the

product redispensed has not been falsified.

By way of derogation from Article 58 and the delegated acts referred to in Article 67(2),

medicinal products that are redispensed shall not be regarded as falsified medicines, and

shall not re-enter the European Medicines Verification System (EMVS). The

information on the safety features contained in the repositories referred to in Article

67(2) point (e) shall not be modified upon collection and re-dispensing of a medicinal

product.

This Article shall not apply to Mmedicinal products that are offered through sale at a

distance are exempted from this Article.

Member States shall notify to the Commission the national rules they implement within

the scope of this Article.

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Article 208

Declaration of interests

In order to guarantee independence and transparency, the Member States shall ensure that

members of staff of the competent authority responsible for granting authorisations,

rapporteurs and experts concerned with the authorisation and surveillance of medicinal

products have no financial or other interests in the pharmaceutical industry that could affect

their impartiality. These persons shall make an annual declaration of their financial interests.

In addition, the Member States shall ensure that the competent authority makes publicly

available its rules of procedure and those of its medicinal products’ authorisation

committees, agendas for its meetings and records of its meetings, accompanied by decisions

taken, details of votes and explanations of votes, including minority opinions.

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Chapter XVII

Specific provisions concerning Cyprus, Ireland, Malta and the United

Kingdom in respect of Northern Ireland

Article 209

Provisions relevant to the United Kingdom in respect of Northern Ireland

By way of derogation from Article 5, the competent authorities of the United Kingdom in

respect of Northern Ireland may temporarily authorise the supply to patients in Northern

Ireland of a medicinal product belonging to the categories referred to in Article 3, paragraphs

1 and 2 of [revised Regulation (EC) No 726/2004] provided that all of the following

conditions are fulfilled:

(a) the medicinal product concerned has been granted a marketing authorisation by the

competent authority of the United Kingdom for parts of the United Kingdom other than

Northern Ireland;

(b) the medicinal product concerned is only made available to patients or end-consumers in

the territory of Northern Ireland and is not made available in any Member State.

The maximum validity of the temporary authorisation shall be six months.

Notwithstanding the specified validity, the temporary authorisation shall cease to be valid if

the medicinal product concerned has been granted a marketing authorisation in accordance

with Article 13 of [revised Regulation (EC) No 726/2004], or if such marketing authorisation

has been refused in accordance with that Article.

By way of derogation from Article 56(46), marketing authorisations may be granted by the

competent authorities of the United Kingdom in respect of Northern Ireland:

(a) to applicants established in parts of the United Kingdom other than Northern Ireland;

(b) to marketing authorisation holders established in parts of the United Kingdom other

than Northern Ireland, in accordance with the mutual recognition or the decentralised

procedure laid down in Chapter III, Sections 3 and 4.

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The competent authorities of the United Kingdom in respect of Northern Ireland may extend

marketing authorisations already granted prior to 20 April 2022 to marketing authorisation

holders established in parts of the United Kingdom other than Northern Ireland.

By way of derogation from Article 33, paragraphs 1, 3 and 4 and Article 35(1), if an

application for marketing authorisation is submitted in one or more Member States and in the

United Kingdom in respect of Northern Ireland, or if an application for marketing

authorisation is submitted in the United Kingdom in respect of Northern Ireland for a

medicinal product that is already being examined or has already been authorised in a Member

State, the application regarding the United Kingdom in respect of Northern Ireland shall not

have to be submitted in accordance with Chapter III, Sections 3 and 4, provided that all of the

following conditions are fulfilled:

(a) the marketing authorisation for the United Kingdom in respect of Northern Ireland is

granted by the competent authority for the United Kingdom in respect of Northern

Ireland in compliance with Union law, and such compliance with Union law is ensured

during the period of validity of that marketing authorisation;

(b) the medicinal products authorised by the competent authority for the United Kingdom in

respect of Northern Ireland are made available to patients or end-consumers only in the

territory of Northern Ireland, and they are not made available in any Member State.

The marketing authorisation holder of a medicinal product for which a marketing

authorisation has already been granted for the United Kingdom in respect of Northern Ireland

in accordance with Chapter III, Sections 3 and 4, before 20 April 2022 shall be allowed to

withdraw the marketing authorisation for the United Kingdom in respect of Northern Ireland

from the mutual recognition or the decentralised procedure and to submit an application for a

marketing authorisation for that medicinal product to the competent authorities of the United

Kingdom with respect to Northern Ireland in accordance with paragraph 13.

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With regard to quality control testing referred to in Article 8 carried out in parts of the United

Kingdom other than Northern Ireland regarding medicinal products included in the list

referred to in Article 20911(910) other than those authorised by the Commission, the

competent authorities of the United Kingdom in respect of Northern Ireland may consider that

there is a justifiable case within the meaning of Article 8, point (b), without carrying out a

case-by-case assessment provided that:

(a) each batch of the medicinal products concerned is released by a qualified person on a

site in the Union or in Northern Ireland or by a qualified person on a site in parts of the

United Kingdom other than Northern Ireland applying quality standards that are

equivalent to those laid down in Article 153;

(b) the establishment designated by the third party conducting the quality control testing is

supervised by the competent authority of the United Kingdom, including by performing

on-the-spot checks;

parts of the United Kingdom other than Northern Ireland, the manufacturing

authorisation holder declares that it does not have at its disposal a qualified person who

residesd and operateds in the Union on 20 April 2022.

By way of derogation from Article 142(1), the competent authorities of the United Kingdom

in respect of Northern Ireland shall allow medicinal products to be imported from parts of the

United Kingdom other than Northern Ireland by a wholesale distribution authorisation holders

as referred to in Article 163(1) that are not in possession of a relevant manufacturing

authorisation provided that all of the following conditions are fulfilled:

(a) the medicinal products have undergone quality control testing either in the Union, as

provided for in Article 153(3), or in parts of the United Kingdom other than Northern

Ireland in compliance with Article 8, point (b);

(b) the medicinal products have been subject to batch release by a qualified person in the

Union in accordance with Article 153(1) or, for medicinal products authorised by the

United Kingdom in respect of Northern Ireland, in parts of the United Kingdom other

than Northern Ireland applying quality standards that are equivalent to those laid down

in Article 153(1);

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accordance with Union law, by the competent authority of a Member State or by the

Commission or, as regards medicinal products placed on the market in Northern Ireland,

by the competent authority of the United Kingdom in respect of Northern Ireland;

(d) medicinal products are only made available to patients or end-consumers in the Member

State into which the medicinal products are imported, or, if imported into Northern

Ireland, are only made available to patients or end-consumers in Northern Ireland;

(e) the medicinal products bear the safety features referred to in Article 67.

For batches of medicinal products that are exported to parts of the United Kingdom other than

Northern Ireland from a Member State and subsequently imported into Northern Ireland, the

controls upon importation referred to in Article 153(1), first and second subparagraphs, shall

not be required, provided that those batches have undergone such controls in a Member State

prior to being exported to parts of the United Kingdom other than Northern Ireland and that

they are accompanied by the control reports referred to in Article 153(1), third subparagraph.

Where the manufacturing authorisation is granted by the competent authority of the United

Kingdom in respect of Northern Ireland, the qualified person referred to in Article 151(1) may

reside and operate in parts of the United Kingdom other than Northern Ireland. This paragraph

shall not apply where the manufacturing authorisation holder already has at its disposal a

qualified person who residesd and operatesd in the Union on 20 April 2022.

By way of derogation from the Article 99(5), where the marketing authorisation is granted by

the competent authority of United Kingdom in respect of Northern Ireland, the qualified

person referred to in Article 99(4), point (a), may reside and operate in parts of the United

Kingdom other than Northern Ireland. This paragraph shall not apply where the marketing

authorisation holder already has at its disposal a qualified person who residesd and operatesd

in the Union on 20 April 2022.

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10. The competent authorities of the United Kingdom in respect of Northern Ireland shall publish

on their website a list of medicinal products to which they have applied or intend to apply the

derogations as set out in this Article and shall ensure that the list is updated and managed in

an independent manner, at least on a six-monthly basis.

Article 210

Regulatory functions carried out in the United Kingdom

The Commission shall continuously monitor developments in the United Kingdom that could

affect the level of protection regarding the regulatory functions referred to in Article 99(4),

Article 151(3), Article 211, paragraphs 1, 2, 5 and 6, Article 209, paragraphs 6 and 7, that are

carried out in parts of the United Kingdom other than Northern Ireland taking into account, in

particular, the following elements:

(a) the rules governing the granting of marketing authorisations, the obligations of the

marketing authorisation holder, the granting of manufacturing authorisations, the

obligations of the manufacturing authorisation holder, the qualified persons and their

obligations, quality control testing, batch release and pharmacovigilance as laid down in

United Kingdom law;

(b) whether the competent authorities of the United Kingdom ensure the effective

enforcement within their territory of the rules referred to in point (a), by means of, inter

alia, inspections and audits of marketing authorisation holders, manufacturing

authorisation holders and wholesale distributors located in their territories, and on-the-

spot checks at their premises regarding the exercise of the regulatory functions referred

to in point (a).

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Where the Commission finds that the level of protection of public health ensured by the

United Kingdom through rules governing the production, distribution and use of medicinal

products as well as the effective enforcement of those rules is no longer essentially equivalent

to that guaranteed within the Union, or where sufficient information is not available to the

Commission to enable it to establish whether an essentially equivalent level of protection of

public health is ensured by the United Kingdom, the Commission shall inform the United

Kingdom through a written notification of that finding and of the detailed reasons therefor.

For a period of six months following the written notification made pursuant to the first

subparagraph, the Commission shall enter into consultations with the United Kingdom with a

view to remedying the situation giving rise to that written notification. In justified cases, the

Commission may extend that period by three months.

If the situation giving rise to the written notification made pursuant to paragraph 2, first

subparagraph, is not remedied within the time limit referred to in paragraph 2, second

subparagraph, the Commission shall be empowered to adopt a delegated act amending or

supplementing the provisions among those referred to in paragraph 1 whose application shall

be suspended.

Where a delegated act pursuant to paragraph 3 has been adopted, the provisions referred to in

the introductory sentence of paragraph 1 as specified in the delegated act shall cease to apply

on the first day of the month following the entry into force of the delegated act.

Where the situation giving rise to the adoption of the delegated act pursuant to paragraph 3

has been remedied, the Commission shall adopt a delegated act specifying those suspended

provisions that shall apply again. In that case, the provisions specified in the delegated act

adopted pursuant to this paragraph shall apply again on the first day of the month following

the entry into force of the delegated act referred to in this paragraph.

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Article 211

Provisions relevant to Cyprus, Ireland and Malta and applicable until 31 December 2024

By way of derogation from Article 56(4), marketing authorisations may be granted in

accordance with the mutual recognition or the decentralised procedure laid down in Chapter

III, Sections 3 and 4, to marketing authorisation holders established in parts of the United

Kingdom other than Northern Ireland.

Until 31 December 2024, the competent authorities of Cyprus, Ireland and Malta marketing

authorisations already granted prior to 20 April 2022 may be extended to marketing

authorisation holders established in parts of the United Kingdom other than Northern Ireland.

The marketing authorisations granted or extended by the competent authorities of Cyprus,

Ireland or Malta in accordance with the first and second subparagraphs or Article 8 (2b) of

Directive 2001/83/EC shall cease to be valid at the latest on 31 December 2026.

With regard to quality control testing referred to in Article 8 carried out in parts of the United

Kingdom other than Northern Ireland regarding medicinal products included in the list

referred to in paragraph 9, other than those authorised by the Commission, and, until 31

December 2024, the competent authorities of Cyprus, Ireland and Malta may consider that

there is a justifiable case within the meaning of Article 8, point (b), without carrying out a

case-by-case assessment provided that:

(a) each batch of the medicinal products concerned is released by a qualified person on a

site in the Union or in Northern Ireland or by a qualified person on a site in parts of the

United Kingdom other than Northern Ireland applying quality standards that are

equivalent to those laid down in Article 153(1);

(b) the establishment designated by the third party conducting the quality control testing is

supervised by the competent authority of the United Kingdom, including by performing

on-the-spot checks;

parts of the United Kingdom other than Northern Ireland, the manufacturing

authorisation holder declares that it does not have at its disposal a qualified person who

resides and operates in the Union on 20 April 2022.

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By way of derogation from Article 142(1), the competent authorities of Cyprus, Ireland and

Malta shall allow medicinal products to be imported from parts of the United Kingdom other

than Northern Ireland by wholesale distribution authorisation holders as referred to in Article

163(1) that are not in possession of a relevant manufacturing authorisation provided that all of

the following conditions are fulfilled:

(a) the medicinal products have undergone quality control testing either in the Union, as

provided for in Article 153(3), or in parts of the United Kingdom other than Northern

Ireland in compliance with Article 8, point (b);

(b) the medicinal products have been subject to batch release by a qualified person in the

Union in accordance with Article 153(1) or, for medicinal products authorised by the

competent authorities the United Kingdom in respect of Northern Ireland, in parts of the

United Kingdom other than Northern Ireland applying quality standards that are

equivalent to those laid down in Article 153(1);

accordance with Union law, by the competent authority of a Member State or by the

Commission or, as regards medicinal products placed on the market in Northern Ireland,

by the competent authority of the United Kingdom in respect of Northern Ireland;

(d) medicinal products are only made available to patients or end-consumers in the Member

State into which the medicinal products are imported, or, if imported into Northern

Ireland, are only made available to patients or end-consumers in Northern Ireland;

(e) the medicinal products bear the safety features referred to in Article 67.

Article 166(1), point (b), shall not apply to imports that fulfil the conditions laid down in the

first subparagraph.

For batches of medicinal products that are exported to parts of the United Kingdom other than

Northern Ireland from a Member State and subsequently imported until 31 December 2024

into Cyprus, Ireland or Malta, the controls upon importation referred to Article 153(1), first

and second subparagraphs, shall not be required, provided that those batches have undergone

such controls in a Member State prior to being exported to parts of the United Kingdom other

than Northern Ireland and that they are accompanied by the control reports referred to in

Article 153(1), third subparagraph.

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By way of derogation from Article 205(1) until 31 December 2024, in the absence of a

marketing authorisation or of a pending application for a marketing authorisation the

competent authorities of Cyprus and Malta may authorise for justified public health reasons

the placing on their national market of a medicinal product authorised in parts of the United

Kingdom other than Northern Ireland.

The competent authorities of Cyprus and Malta may also maintain in force or, until 31

December 2024, extend marketing authorisations that were granted pursuant to Article 205(1)

before 20 April 2022 and that authorise the placing on their national market of a medicinal

product authorised in parts of the United Kingdom other than Northern Ireland.

Authorisations that are granted, extended or maintained in force pursuant to the first or second

subparagraphs shall not be valid after 31 December 2026.

By way of derogation from Article 56(4), the competent authorities of Malta and Cyprus may

grant marketing authorisations as referred to in paragraph 5 to marketing authorisation holders

established in parts of the United Kingdom other than Northern Ireland.

Where the competent authorities of Cyprus or Malta grant or extend a marketing authorisation

as referred to in paragraph 5, they shall ensure compliance with the requirements of this

Directive.

Before granting a marketing authorisation pursuant to paragraph 5, the competent authorities

of Cyprus or Malta:

(a) shall notify the marketing authorisation holder in parts of the United Kingdom other

than Northern Ireland of the proposal to grant a marketing authorisation or to extend a

marketing authorisation under paragraphs 5 to 8 in respect of the medicinal product

concerned;

(b) may request the competent authority in the United Kingdom to submit the relevant

information regarding the marketing authorisation of the medicinal product concerned.

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The competent authorities of Cyprus, Ireland, Malta shall publish on their website a list of

medicinal products to which they have applied or intend to apply the derogations as set out in

this Article and shall ensure that the list is updated and managed in an independent manner, at

least on a six-monthly basis.

Article 212

Derogations for medicinal products placed on the markets of Cyprus, Ireland, Malta or Northern

Ireland

The derogations set out in Article 211, paragraphs 1 and 6, Article 8, Article 209, paragraphs 3, 6

and 7, and 8 Article 153 (3), Article 99(4) and Article 211(5) shall not affect the obligations of the

marketing authorisation holder to ensure the quality, safety and efficacy of the medicinal product

placed on the markets of Cyprus, Ireland, Malta or Northern Ireland laid down in this Directive.

Chapter XVIII

Final provisions

Article 213

Amendment to the Annexes

The Commission is empowered to adopt delegated acts in accordance with Article 215 amending

Annexes I to VI in order to adapt them to scientific and technical progress and amend Article 22

with regard to the ERA requirements set out in paragraphs 2, 3, 4 and 6 of that Article.

Article 214

Standing Committee on Medicinal Products for Human Use

The Commission shall be assisted by the Standing Committee on Medicinal Products for

Human Use. That Committee shall be a committee within the meaning of Regulation (EU) No

182/2011.

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Where reference is made to this paragraph, Article 5 of Regulation (EU) No 182/2011 shall

apply.

Where the opinion of the Committee is to be obtained by written procedure and reference is

made to this paragraph, that procedure shall be terminated without result only when, within

the time limit for delivery of the opinion, the chair of the Committee so decides.

The rules of procedure of the Standing Committee on Medicinal Products shall be made

publicly available.

The Standing Committee on Medicinal Products for Human Use shall ensure that its rules of

procedure are adapted to the need to make medicinal products swiftly available to patients and

take account of the tasks incumbent upon it under Chapter III and the procedure set out in

Article 42.

Article 215

Exercise of the delegations

The power to adopt delegated acts is conferred on the Commission subject to the conditions

laid down in this Article.

The power to adopt delegated acts referred to in Articles 4(2), 24(5), 25(9), 26(3), 28,

paragraphs 2 and 3, 27(3), 63(5), 65(2), 67(2), 88(1), 92(4), 126(1), 150(3), 153(4), 161,

210(4) and 213 shall be conferred on the Commission for a period of five years from [OP

please insert the date of the entry into force of this Directive]. The Commission shall draw up

a report in respect of the delegation of power not later than nine months before the end of the

five-year period. The delegation of power shall be tacitly extended for periods of an identical

duration, unless the European Parliament or the Council opposes such extension not later than

three months before the end of each period.

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The power to adopt delegated acts referred to in Article 210, paragraphs 3 and 5, shall be

conferred on the Commission for an indeterminate period of time from [OP please insert the

date = the date of the entry into force of this Directive].

The delegation of power referred to in Articles 4(2), 24(5), 25(9), 26(3), 27(3), 28, paragraphs

2 and 3, 63(5), 65(2), 67(2), 88(1), 92(4), 126(1), 150(3), 153(4), 161, 210(4) and 213 may be

revoked at any time by the European Parliament or by the Council. A decision to revoke shall

put an end to the delegation of the power specified in that decision. It shall take effect the day

following the publication of the decision in the Official Journal of the European Union or at a

later date specified therein. It shall not affect the validity of any delegated acts already in

force.

Before adopting a delegated act, the Commission shall consult experts designated by each

Member State in accordance with the principles laid down in the Interinstitutional Agreement

of 13 April 2016 on Better Law-Making.

As soon as it adopts a delegated act, the Commission shall notify it simultaneously to the

European Parliament and to the Council.

A delegated act adopted pursuant to Articles 6(2), 26(3), 24(5), 28, paragraphs 2 and 3, 27(3),

63(5), 65(2), 67(2), 88(1), 92(4), 126(1), 150(3), 153(4), 161, 210(4) and 213 shall enter into

force only if no objection has been expressed either by the European Parliament or by the

Council within a period of two months of notification of that act to the European Parliament

and the Council or if, before the expiry of that period, the European Parliament and the

Council have both informed the Commission that they will not object. That period shall be

extended by two months at the initiative of the European Parliament or of the Council.

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Article 216

Report

By [OP please insert the date = 10 years following 18 36 months after the date of entering into

force of this Directive], the Commission shall present a report to the European Parliament and

the Council on the application of this Directive, including an assessment of the fulfilment of

its objectives and the resources required to implement it.

By [OP please insert the date = 6 years following the date of entering into force of this

Directive], the Commission shall present a report to the European Parliament and the

Council on the application of Article 56a. The report shall be, based, among others, on

information provided by Member States, and it shall include an assessment on whether

the rules provided for in that Article ensures timely availability and continuous supply

of medicinal products in a sufficient quantity in all Member States that have applied

that Article. The Commission shall, if appropriate, present legislative proposals based

on that evaluation in order to amend this Directive or make further proposals.

Article 217

Repeals

Directive 2001/83/EC is repealed with effect from [OP please insert the date = 18 36 months

after the date of entering into force of this Directive].

Directive 2009/35/EC is repealed with effect from [OP please insert the date = 18 36 months

after the date of entering into force of this Directive].

References to the repealed Directives 2001/83/EC and 2009/35/EC shall be construed as

references to this Directive. References to the repealed Directive 2001/83/EC shall be read in

accordance with the correlation table in Annex VIII.

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Article 218

Transitional provisions

The procedures concerning the applications for marketing authorisations for medicinal

products validated in accordance with Article 19 of Directive 2001/83/EC before [OP please

insert the date = 18 36 months after the date of entering into force of this Directive] and that

were pending on [OP please insert the date = the day before 18 36 months after the date of

entering into force of this Directive] shall be completed in accordance with Directive

2001/83/ECArticle 29.

Procedures initiated on the basis of Articles 29, 30, 31, and 107i of Directive 2001/83/EC

before [OP please insert the date = 18 36 months after the date of entering into force of this

Directive] and that were pending on [OP please insert the date = the day before 18 36 months

after the date of entering into force of this Directive] shall be completed in accordance with

Articles 32 to 34 or Article 107k, as appropriate, of that Directive as applicable on [OP please

insert the date = the day before 18 36 months after the date of entering into force of this

Directive].

This Directive shall also apply to medicinal products authorised in accordance with Directive

2001/83/EC before [OP please insert the date = 18 36 months after the date of entering into

force of this Directive].

This Directive shall also apply to registrations of homeopathic medicinal products and

traditional herbal medicinal products carried out in accordance with Directive 2001/83/EC

before [OP please insert the date = 18 36 months after the date of entering into force of this

Directive].

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By way of derogation from Chapter VI, the medicinal products placed on the market in

accordance with Directive 2001/83/EC before [OP please insert the date = 18 36 months after

the date of entering into force of this Directive] may continue to be made available on the

market until [OP please insert the date = five years after 18 36 months after the date of

entering into force of this Directive], provided that they comply with the provision on

labelling and package leaflet set out in Title V of Directive 2001/83/EC as applicable on [OP

please insert the date = the day before 18 36 months after the date of entering into force of

this Directive].

By way of derogation from Article 81, reference medicinal products for which the application

for marketing authorisation has been submitted before [OP please insert the date = 18 36

months after the date of entering into force of this Directive] shall be subject to the provisions

on data protection periods set out in Article 10 of Directive 2001/83/EC as applicable on [OP

please insert the date = 18 36 months after the date of entering into force of this Directive]

until [OP please insert the date = 18 36 months after the date of entering into force of this

Directive].

By way of derogation from paragraph 3, the reporting obligations as referred to in Article 57,

shall not apply with regards to medicinal products authorised in accordance with Directive

2001/83/EC before [OP please insert the date = 18 36 months after the date of entering into

force of this Directive].

6a. For medicinal products authorised before [OP please insert the date the date of entering

into force application of this Directive] and for which the validity expires after that date,

the renewal of the marketing authorisation shall follow the procedures referred to in

Article 46.

6b. Medicinal products placed on the market prior to [36 months after the date of entering

into force of this Directive] which do not comply with the requirements of this Directive

may be marketed until the stocks of the medicinal products are exhausted.

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The requirement to make the package leaflet available electronically, pursuant to

Article 63, paragraph 1 shall apply as follows:

(a) for medicinal products for which the application for marketing authorisation was

submitted after [OP please insert the date of entering into application], it shall

apply immediately, provided that the implementing act referred to in Article 63(6)

is adopted;

(b) for medicinal products authorised before [OP please insert the date the date of

entering into force of this Directive] and medicinal products for which the

application for marketing authorisation was submitted before [OP please insert

the date of entering into application], it shall apply on [OP please insert the date =

3 years after the date of entering into application of this Directive], unless a

marketing authorisation holder chooses to comply with the requirement earlier

and provided that the implementing act mentioned in Article 63(6) is adopted.

Medicinal products produced, packaged and labelled prior to [OP please insert the date

the date of entering into force of this Directive] which do not comply with the

requirement to make the package leaflet available electronically, pursuant to Article 63,

paragraph 1 may continue to be placed on the market, distributed, dispensed, sold and

used until stocks of those medicinal products are exhausted.

The marketing authorisations granted by Malta or Cyprus on a basis of Article 126a of

Directive 2001/83/EC and maitained in force by Cyprus and Malta on a basis of Article

126(1)c of Directive 2001/83/EC shall be valid until 31 December 2026.

Article 219

Transposition

Member States shall bring into force the laws, regulations and administrative provisions to

comply with this Directive by [18 36 months after the date of entering into force of this

Directive]. They shall immediately communicate the text of those measures to the

Commission. Member States shall apply those provisions from [36 months after the date

of entering into force of this Directive].

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However Member States may apply Article 56a from an earlier date in respect of

medicinal products authorised after the date of entering into force of this Directive. In

case of a medicinal product which has been granted a marketing authorisation in

accordance with Regulation 726/2004 or the Directive 2001/83 between the entry into

force and the date of application of this Directive, the second subparagraph of Article 10

(1) of the Directive 2001/83 shall not apply in the member state that made a request in

accordance with Article 56a, if the marketing authorisation holder has not made the

medicinal product available and has not supplied it continuously in that Member State

in accordance with that Article.

When Member States adopt those measures, they shall contain a reference to this Directive or

be accompanied by such reference on the occasion of their official publication. They shall

also include a statement that references in existing laws, regulations and administrative

provisions to the Directives repealed by this Directive shall be construed as references to this

Directive. Member States shall determine how such reference is to be made and how that

statement is to be formulated.

Member States shall communicate to the Commission the text of the main measures of

national law that they adopt in the field covered by this Directive.

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Article 220

Entry into force

This Directive shall enter into force on the twentieth day following that of its publication in the

Official Journal of the European Union.

Article 221

Addressees

This Directive is addressed to the Member States.

Done at Brussels,

For the European Parliament

For the Council

The President

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ANNEX TO THE ANNEX

ANNEX I

INFORMATION REFERRED TO IN THE APPLICATION

(1) Name or corporate name and permanent address of the applicant and, where applicable, of the

manufacturer.

(2) Name of the medicinal product.

(3) Qualitative and quantitative particulars of all the constituents of the medicinal product,

including the reference to its international non-proprietary name (INN) recommended by the

World Health Organization, where an INN for the medicinal product exists, or a reference to

the relevant chemical name.

(4) An environmental risk assessment (ERA) in accordance with the requirements laid down in

Articles 22 and 23.

(5) For medicinal product for human use containing or consisting of genetically modified

organisms, an environmental risk assessment identifying and characterising possible hazards

for human health, animals and the environment. The assessment shall be conducted in

accordance with the elements described in Article 8 of [revised Regulation (EC) No

726/2004] and the requirements of Annex II to this Directive, based on the principles set out

in Annex II to Directive 2001/18/EC of the European Parliament and of the Council47 taking

into account the specificities of medicinal products.

(6) Description of the manufacturing method.

(7) Therapeutic indications, contra-indications and adverse reactions.

Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the
deliberate release into the environment of genetically modified organisms and repealing Council
Directive 90/220/EEC - Commission Declaration (OJ L 106, 17.4.2001, p. 1)

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(8) Posology, pharmaceutical form, method and route of administration and expected shelf life.

(9) Reasons for any precautionary and safety measures to be taken for the storage of the

medicinal product, its administration to patients and for the disposal of waste products,

together with an indication of potential risks presented by the medicinal product for the

environment.

(10) Description of the control methods employed by the manufacturer.

(11) A written confirmation that the manufacturer of the medicinal product has verified

compliance of the manufacturer of the active substance with principles of good manufacturing

practice by conducting audits, in accordance with Article 160. The written confirmation shall

contain a reference to the date of the audit and a declaration that the outcome of the audit

confirms that the manufacturing complies with the principles of good manufacturing practice.

(12) Results of:

(a) pharmaceutical (physico-chemical, biological or micro biological) tests,

(b) non-clinical (toxicological and pharmacological) tests,

(13) Where relevant, evidence from other sources of clinical data (non-interventional clinical

studies, registries).

(14) A summary of the applicant’s pharmacovigilance system which shall include the following

elements:

(a) proof that the applicant has at their disposal a qualified person responsible for

pharmacovigilance,

(b) the Member States in which the qualified person resides and carries out their tasks,

(d) a statement signed by the applicant to the effect that the applicant has the necessary

means to fulfil the tasks and responsibilities listed in Chapter VI,

(e) a reference to the location where the pharmacovigilance system master file for the

medicinal product is kept.

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(15) The risk management plan describing the risk management system which the applicant will

introduce for the medicinal product concerned, together with a summary thereof.

(16) A statement to the effect that clinical trials carried out outside the European Union meet the

ethical requirements of Regulation (EU) No 536/2014.

(17) A summary of product characteristics in accordance with Article 62, a mock-up of the outer

packaging, containing the details provided for in Annex IV, and of the immediate packaging

of the medicinal product, containing the details provided for in Article 66, together with a

package leaflet in accordance with Article 64.

(18) A document showing that the manufacturer is authorised in their own country to produce

medicinal products.

(19) Copies of the following:

(a) any marketing authorisation, obtained in another Member State or in a third country, to

place the medicinal product on the market, a summary of the safety data including the

data contained in the periodic safety update reports, where available, and suspected

adverse reactions reports, together with a list of those Member States in which an

application for marketing authorisation submitted in accordance with this Directive is

under examination;

(b) the summary of product characteristics proposed by the applicant in accordance with

Article 62 or approved by the competent authorities of the Member State in accordance

with Article 43 and the package leaflet proposed in accordance with Article 64 or

approved by the competent authorities of the Member State in accordance with Article

76;

third country, and the reasons for such a decision.

(20) A copy of any designation of the medicinal product as an orphan medicinal product as defined

in Article 63 of [revised Regulation (EC) No 726/2004], accompanied by a copy of the

relevant Agency opinion.

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(21) Where the application concerns an antimicrobial medicinal product, the application shall also

contain:

(a) an antimicrobial stewardship plan which shall in particular outline:

(i)

information about risk mitigation measures to limit antimicrobial resistance

development related to the use, prescription and administration of the medicinal

product;

(ii) how the marketing authorisation holder intends to monitor and report to the

competent authority the resistance to the antimicrobial medicinal product.

(b) a description of the special information requirements outlined in Article 58

treatment.

(22) Where an application concerns the marketing authorisation to market a radionuclide

generator, in addition to the requirements set out in Articles 6 and 9, it shall also contain:

(a) a general description of the system together with a detailed description of the

components of the system that may affect the composition or quality of the daughter

nucleid preparation; and

(b) qualitative and quantitative particulars of the eluate or the sublimate.

(23) Good manufacturing practices certificates.

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ANNEX II

ANALYTICAL, PHARMACOTOXICOLOGICAL AND CLININCAL STANDARDS AND

PROTOCOLS IN RESPECT OF THE TESTING OF MEDICINAL PRODUCTS

TABLE OF CONTENTS

Introduction and general principles

Part I:

Standardised marketing authorisation dossier requirements

Module 1: Administrative information

1.1.

Table of contents

1.2.

Application form

1.3.

Summary of product characteristics, labelling and package leaflet

1.3.1.

Summary of product characteristics

1.3.2.

Labelling and package leaflet

1.3.3.

Mock-ups and specimens

1.3.4.

Summaries of product characteristics already approved in the Member States

1.4.

Information about the experts

1.5.

Specific requirements for different types of applications

1.6.

Environmental risk assessment

Module 2: Summaries

2.1.

Overall table of contents

2.2.

Introduction

2.3.

Quality overall summary

2.4.

Non-clinical overview

2.5.

Clinical overview

2.6.

Non-clinical summary

2.7.

Clinical Summary

Module 3: Chemical, pharmaceutical and biological information for medicinal

products containing chemical and/or biological active substances

3.1.

Format and presentation

3.2.

Content: basic principles and requirements

3.2.1.

Active substance(s)

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3.2.1.1.

General information and information related to the starting and raw materials

3.2.1.2.

Manufacturing process of the active substance(s)

3.2.1.3.

Characterisation of the active substance(s)

3.2.1.4.

Control of active substance(s)

3.2.1.5.

Reference standards or materials

3.2.1.6.

Container and closure system of the active substance

3.2.1.7.

Stability of the active substance(s)

3.2.2.

Finished medicinal product

3.2.2.1.

Description and composition of the finished medicinal product

3.2.2.2.

Pharmaceutical development

3.2.2.3.

Manufacturing process of the finished medicinal product

3.2.2.4.

Control of excipients

3.2.2.5.

Control of the finished medicinal product

3.2.2.6.

Reference standards or materials

3.2.2.7.

Container and closure of the finished medicinal product

3.2.2.8.

Stability of the finished medicinal product

Module 4: Non-clinical reports

4.1.

Format and Presentation

4.2.

Content: basic principles and requirements

4.2.1.

Pharmacology

4.2.2.

Pharmaco-kinetics

4.2.3.

Toxicology

Module 5: Clinical study reports

5.1.

Format and Presentation

5.2.

Content: basic principles and requirements

5.2.1.

Reports of bio-pharmaceutics studies

5.2.2.

Reports of studies pertinent to pharmaco-kinetics using human bio-materials

5.2.3.

Reports of human pharmaco-kinetic studies

5.2.4.

Reports of human pharmaco-dynamic studies

5.2.5.

Reports of efficacy and safety studies

5.2.5.1.

Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication

5.2.5.2.

Study reports of uncontrolled clinical studies reports of analyses of data from more

than one study and other clinical study reports

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5.2.6.

Reports of post-marketing experience

5.2.7.

Case reports forms and individual patient listings

Part II:

Specific marketing authorisation dossiers and requirements

Well- established medicinal use

Essentially similar medicinal products

Additional data required in specific situations

Similar biological medicinal products

Fixed combination medicinal products

Documentation for applications in exceptional circumstances

Mixed marketing authorisation applications

Part III:

Particular medicinal products

Biological medicinal products

1.1.

Plasma-derived medicinal product

1.2.

Vaccines

Radio-pharmaceuticals and precursors

2.1.

Radio-pharmaceuticals

2.2.

Radio-pharmaceutical precursors for radio-labelling purposes

Homeopathic medicinal products

Herbal medicinal products

Orphan Medicinal Products

Part IV:

Advanced therapy medicinal products

Introduction

Definitions

2.1.

Gene therapy medicinal product

2.2.

Somatic cell therapy medicinal product

Specific requirements regarding Module 3

3.1.

Specific requirements for all advanced therapy medicinal products

3.2.

Specific requirements for gene therapy medicinal products

3.2.1.

Introduction: finished product, active substance and starting materials

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3.2.1.1.

Gene therapy medicinal product containing recombinant nucleic acid sequence(s) or

genetically modified microorganism(s) or virus(es)

3.2.1.2.

Gene therapy medicinal product containing genetically modified cells

3.2.2.

Specific requirements

3.3.

Specific requirements for somatic cell therapy medicinal products and tissue

engineered products

3.3.1.

Introduction: finished product, active substance and starting materials

3.3.2.

Specific requirements

3.3.2.1.

Starting materials

3.3.2.2.

Manufacturing process

3.3.2.3.

Characterisation and control strategy

3.3.2.4.

Excipients

3.3.2.5.

Developmental studies

3.3.2.6.

Reference materials

3.4.

Specific requirements for advanced therapy medicinal products containing devices

3.4.1.

Advanced therapy medicinal product containing devices as referred to in Article 7 of

Regulation (EC) No 1394/2007

3.4.2.

Combined advanced therapy medicinal products as defined in Article 2(1)(d) of

Regulation (EC) No 1394/2007

Specific requirements regarding module 4

4.1.

Specific requirements for all advanced therapy medicinal products

4.2.

Specific requirements for gene therapy medicinal products

4.2.1.

Pharmacology

4.2.2.

Pharmacokinetics

4.2.3.

Toxicology

4.3.

Specific requirements for somatic cell therapy medicinal products and tissue

engineered products

4.3.1.

Pharmacology

4.3.2.

Pharmacokinetics

4.3.3.

Toxicology

Specific requirements regarding module 5

5.1.

Specific requirements for all advanced therapy medicinal products

5.2.

Specific requirements for gene therapy medicinal products

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5.2.1.

Human pharmacokinetic studies

5.2.2.

Human pharmacodynamic studies

5.2.3.

Safety studies

5.3.

Specific requirements for somatic cell therapy medicinal products

5.3.1.

Somatic cell therapy medicinal products where the mode of action is based on the

production of defined active biomolecule(s)

5.3.2.

Biodistribution, persistence and long-term engraftment of the somatic cell therapy

medicinal product components

5.3.3.

Safety studies

5.4.

Specific requirements for tissue engineered products

5.4.1.

Pharmacokinetic studies

5.4.2.

Pharmacodynamic studies

5.4.3.

Safety studies

Introduction and general principles

(1) The particulars and documents accompanying an application for marketing authorisation

pursuant to Articles 8 and 10(1) shall be presented in accordance with the requirements set out

in this Annex and shall follow the guidance published by the Commission in The rules

governing medicinal products in the European Community, Volume 2 B, Notice to applicants,

Medicinal products for human use, Presentation and content of the dossier, Common Technical

Document (CTD).

(2) The particulars and documents shall be presented as five modules: Module 1 provides European

Community specific administrative data; Module 2 provides quality, non-clinical and clinical

summaries, Module 3 provides chemical, pharmaceutical and biological information, Module

4 provides non-clinical reports and Module 5 provides clinical study reports. This presentation

implements a common format for all ICH (48) regions (European Community, United States of

America, Japan). These five Modules shall be presented in strict accordance with the format,

content and numbering system delineated in details in Volume 2 B of the Notice to Applicants

referred to above.

International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use

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(3) The European Community-CTD-presentation is applicable for all types of marketing

authorisation applications irrespective of the procedure to be applied (i.e. centralised, mutual

recognition or national) and of whether they are based on a full or abridged application. It is

also applicable for all types of products including new chemical entities (NCE), radio-

pharmaceuticals, plasma derivatives, vaccines, herbal medicinal products, etc.

(4) In assembling the dossier for application for marketing authorisation, applicants shall also

take into account the scientific guidelines relating to the quality, safety and efficacy of

medicinal products for human use as adopted by the Committee for Proprietary Medicinal

Products (CPMP) and published by the European Medicine Evaluation Agency (EMEA) and

the other pharmaceutical Community guidelines published by the Commission in the different

volumes of The rules governing medicinal products in the European Community.

(5) With respect to the quality part (chemical, pharmaceutical and biological) of the dossier, all

monographs including general monographs and general chapters of the European

Pharmacopoeia are applicable.

(6) The manufacturing process shall comply with the requirements of Commission Directive

91/356/EEC laying down the principles and guidelines of Good Manufacturing Practice

(GMP) for medicinal products for human use (49) and with the principles and guidelines on

GMP, published by the Commission in The rules governing medicinal products in the

European Community, Volume 4.

(7) All information, which is relevant to the evaluation of the medicinal product concerned, shall

be included in the application, whether favourable or unfavourable to the product. In

particular, all relevant details shall be given of any incomplete or abandoned pharmaco-

toxicological or clinical test or trial relating to the medicinal product and/or completed trials

concerning therapeutic indications not covered by the application.

OJ L 193, 17.7.1991, p. 30

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(8) All clinical trials, conducted within the European Community, must comply with the

requirements of Directive 2001/20/EC of the European Parliament and of the Council on the

approximation of the laws, regulations and administrative provisions of the Member States

relating to the implementation of good clinical practice in the conduct of clinical trials on

medicinal products for human use (50). To be taken into account during the assessment of an

application, clinical trials, conducted outside the European Community, which relate to

medicinal products intended to be used in the European Community, shall be designed,

implemented and reported on what good clinical practice and ethical principles are concerned,

on the basis of principles, which are equivalent to the provisions of Directive 2001/20/EC.

They shall be carried out in accordance with the ethical principles that are reflected, for

example, in the Declaration of Helsinki.

(9) Non-clinical (pharmaco-toxicological) studies shall be carried out in conformity with the

provisions related to Good Laboratory Practice laid down in Council Directives 87/18/EEC on

the harmonisation of regulations and administrative provisions relating to the application of

the principles of good laboratory practice and the verification of their application for tests in

chemical substances (51) and 88/320/EEC on the inspection and verification of good

laboratory practice (GLP) (52).

(10) Member States shall also ensure that all tests on animals are conducted in accordance with

Council Directive 86/609/EEC of 24 November 1986 on the approximation of laws,

regulation and administrative provisions of the Member States regarding the protection of

animals for experimental and other scientific purposes.

OJ L 121, 1.5.2001, p. 34

OJ L 15, 17.1.1987, p. 29

OJ L 145, 11.6.1988, p. 35

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(11) In order to monitor the benefit/risk assessment, any new information not in the original

application and all pharmaco-vigilance information shall be submitted to the competent

authority. After marketing authorisation has been granted, any change to the data in the

dossier shall be submitted to the competent authorities in accordance with the requirements of

Commission Regulations (EC) No 1084/2003 (53) and (EC) No 1085/2003 (54) of the

Commission or, if relevant, in accordance with national provisions, as well as the

requirements in Volume 9 of Commission publication The rules governing medicinal products

in the European Community.

This Annex is divided in four different parts:

Part I describes the application format, the summary of product characteristics, the labelling,

the leaflet and presentation requirements for standard applications (Modules 1 to 5).

Part II provides derogation for ‘Specific applications’, i.e. well-established medicinal use,

essentially similar products, fixed combinations, similar biological products, exceptional

circumstances and mixed applications (part bibliographic and part own studies).

Part III deals with ‘Particular application requirements’ for biological medicinal products

(Plasma Master File; Vaccine Antigen Master File), radio-pharmaceuticals, homeopathic

medicinal products, herbal medicinal products and orphan medicinal products.

Part IV deals with ‘Advanced therapy medicinal products’ and concerns specific requirements

for gene therapy medicinal products (using human autologous or allogeneic system, or

xenogeneic system) and cell therapy medicinal products both of human or animal origin and

xenogeneic transplantation medicinal products.

See p. 1 of this Official Journal

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PART I

STANDARDISED MARKETING AUTHORISATION DOSSIER REQUIREMENTS

MODULE 1: ADMINISTRATIVE INFORMATION

1.1. Table of contents

A comprehensive table of contents of Modules 1 to 5 of the dossier submitted for marketing

authorisation application shall be presented.

1.2. Application form

The medicinal product, which is the subject of the application, shall be identified by name and

name of the active substance(s), together with the pharmaceutical form, the route of

administration, the strength and the final presentation, including packaging.

The name and address of the applicant shall be given, together with the name and address of

the manufacturers and the sites involved in the different stages of the manufacture (including

the manufacturer of the finished product and the manufacturer(s) of the active substance(s)),

and where relevant the name and address of the importer.

The applicant shall identify the type of application and indicate what samples, if any, are also

provided.

Annexed to the administrative data shall be copies of the manufacturing authorisation as

defined in Article 40, together with a list of countries in which authorisation has been granted,

copies of all the summaries of product characteristics in accordance with Article 11 as

approved by Member States and a list of countries in which an application has been

submitted.

As outlined in the application form, the applicants shall provide, inter alia, details of the

medicinal product subject of the application, the legal basis of the application, the proposed

marketing authorisation holder and manufacture(s), information on orphan medicinal product

status, scientific advice and paediatric development program.

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1.3. Summary of product characteristics, labelling and package leaflet

1.3.1. Summary of product characteristics

The applicant shall propose a summary of the product characteristics, in accordance with

Article 11.

1.3.2. Labelling and package leaflet

A proposed labelling text for immediate and outer packaging as well as for the package

leaflet shall be provided. These shall be in accordance with all mandatory items listed in

Title V on the labelling of medicinal products for human use (Article 63) and on package

leaflet (Article 59).

1.3.3. Mock-ups and specimens

The applicant shall provide specimen and/or mock-ups of the immediate and outer

packaging, labels and package leaflets for the medicinal product concerned.

1.3.4. Summaries of product characteristics already approved in the Member States

Annexed to the administrative data of the application form shall be copies of all the

summaries of product characteristics in accordance with Articles 11 and 21 as approved by

Member States, where applicable and a list of countries in which an application has been

submitted.

1.4. Information about the experts

In accordance with Article 12 (2) experts must provide detailed reports of their observations

on the documents and particulars which constitute the marketing authorisation dossier and in

particular on Modules 3, 4 and 5 (chemical, pharmaceutical and biological documentation,

non-clinical documentation and clinical documentation, respectively). The experts are

required to address the critical points related to the quality of the medicinal product and of the

investigations carried out on animals and human beings and bring out all the data relevant for

evaluation.

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These requirements shall be met by providing a quality overall summary, a non-clinical

overview (data from studies carried out in animals) and a clinical overview that shall be

located in Module 2 of the marketing authorisation application dossier. A declaration signed

by the experts together with brief information on their educational background, training and

occupational experience shall be presented in Module 1. The experts shall have suitable

technical or professional qualifications. The professional relationship of the expert to the

applicant shall be declared.

1.5. Specific requirements for different types of applications

Specific requirements for different types of applications are addressed in Part II of the present

Annex.

1.6. Environmental risk assessment

Where applicable, applications for marketing authorisations shall include a risk assessment

overview evaluating possible risks to the environment due to the use and/or disposal of the

medicinal product and make proposals for appropriate labelling provisions. Environmental

risk connected with the release of medicinal products containing or consisting of GMOs

(Genetically Modified Organisms) within the meaning of Article 2 of Directive 2001/18/EC

of the European Parliament and of the Council of 12 March 2001 on the deliberate release

into the environment of modified organisms and repealing Council Directive 90/220/EEC (55)

shall be addressed.

Information pertaining to the environmental risk shall appear as an appendix to Module 1.

The information shall be presented in accordance with the provisions of Directive

2001/18/EC, taking into account any guidance documents published by the Commission in

connection with the implementation of the said Directive.

OJ L 106, 17.4.2001, p. 1

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The information shall consist of:

an introduction;

a copy of any written consent or consents to the deliberate release into the environment

of the GMO(s) for research and development purposes according to Part B of Directive

2001/18/EC;

the information requested in Annexes II to IV of the Directive 2001/18/EC, including

detection and identification methods as well as unique code of the GMO, plus any

additional information on the GMO or the product of relevance to evaluating the

environmental risk;

an environment risk assessment (ERA) report prepared on basis of the information

specified in Annexes III and IV of Directive 2001/18/EC and in accordance with Annex

II of Directive 2001/18/EC;

taking into account the above information and the ERA, a conclusion which proposes an

appropriate risk management strategy which includes, as relevant to the GMO and

product in question, a post-market monitoring plan and the identification of any special

particulars which need to appear in the Summary of Product Characteristics, labelling

and package leaflet;

appropriate measures in order to inform the public.

A dated signature of the author, information on the author's educational, training and

occupational experience, and a statement of the author's relationship with the applicant, shall

be included.

MODULE 2: SUMMARIES

This Module aims to summarise the chemical, pharmaceutical and biological data, the non-clinical

data and the clinical data presented in Modules 3, 4 and 5 of the dossier for marketing authorisation,

and to provide the reports/overviews described in Article 12 of this Directive.

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Critical points shall be addressed and analysed. Factual summaries including tabular formats shall

be provided. Those reports shall provide cross-references to tabular formats or to the information

contained in the main documentation presented in Module 3 (chemical, pharmaceutical and

biological documentation), Module 4 (non-clinical documentation) and Module 5 (clinical

documentation).

Information contained in Module 2 shall be presented in accordance with the format, content and

numbering system delineated in the Volume 2 of the Notice to Applicants. The overviews and

summaries shall comply with the basic principles and requirements as laid down herewith:

2.1. Overall table of contents

Module 2 shall contain a table of contents for the scientific documentation submitted in

Modules 2 to 5.

2.2. Introduction

Information on the pharmacological class, mode of action and proposed clinical use of the

medicinal product for which a marketing authorisation is requested shall be supplied.

2.3. Quality overall summary

A review of the information related to the chemical, pharmaceutical and biological data shall

be provided in a quality overall summary.

Key critical parameters and issues related to quality aspects shall be emphasised as well as

justification in cases where the relevant guidelines are not followed. This document shall

follow the scope and outline of the corresponding detailed data presented in Module 3.

2.4. Non-clinical overview

An integrated and critical assessment of the non-clinical evaluation of the medicinal product

in animals/in vitro shall be required. Discussion and justification of the testing strategy and of

deviation from the relevant guidelines shall be included.

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Except for biological medicinal products, an assessment of the impurities and degradation

products shall be included along with their potential pharmacological and toxicological

effects. The implications of any differences in the chirality, chemical form, and impurity

profile between the compound used in the non-clinical studies and the product to be marketed

shall be discussed.

For biological medicinal products, comparability of material used in non-clinical studies,

clinical studies, and the medicinal product for marketing shall be assessed.

Any novel excipient shall be the subject of a specific safety assessment.

The characteristics of the medicinal product, as demonstrated by the non-clinical studies shall

be defined and the implications of the findings for the safety of the medicinal product for the

intended clinical use in human shall be discussed.

2.5. Clinical overview

The clinical overview is intended to provide a critical analysis of the clinical data included in

the clinical summary and Module 5. The approach to the clinical development of the

medicinal product, including critical study design, decisions related to and performance of the

studies shall be provided.

A brief overview of the clinical findings, including important limitations as well as an

evaluation of benefits and risks based on the conclusions of the clinical studies shall be

provided. An interpretation of the way the efficacy and safety findings support the proposed

dose and target indications and an evaluation of how the summary of product characteristics

and other approaches will optimise the benefits and manage the risks is required.

Efficacy or safety issues encountered in development and unresolved issues shall be

explained.

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2.6. Non-clinical summary

The results of pharmacology, pharmaco-kinetics and toxicology studies carried out in

animals/in vitro shall be provided as factual written and tabulated summaries which shall be

presented in the following order:

Introduction

Pharmacology Written Summary

Pharmacology Tabulated Summary

Pharmaco-kinetics Written Summary

Pharmaco-kinetics Tabulated Summary

Toxicology Written Summary

Toxicology Tabulated Summary.

2.7. Clinical Summary

A detailed, factual summary of the clinical information on the medicinal product included in

Module 5 shall be provided. This shall include the results of all bio-pharmaceutics studies, of

clinical pharmacology studies, and of clinical efficacy and safety studies. A synopsis of the

individual studies is required.

Summarised clinical information shall be presented in the following order:

Summary of Bio-pharmaceutics and Associated Analytical Methods

Summary of Clinical Pharmacology Studies

Summary of Clinical Efficacy

Summary of Clinical Safety

Synopses of Individual Studies

MODULE 3: CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL INFORMATION

FOR MEDICINAL PRODUCTS CONTAINING CHEMICAL AND/OR BIOLOGICAL

ACTIVE SUBSTANCES

3.1. Format and presentation

The general outline of Module 3 is as follows:

— Table of contents

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— Body of data

— Active substance

G e n e r a l I n f o r m a t i o n

— Nomenclature

— Structure

— General Properties

M a n u f a c t u r e

— Manufacturer(s)

— Description of Manufacturing Process and Process Controls

— Control of Materials

— Controls of Critical Steps and Intermediates

— Process Validation and/or Evaluation

— Manufacturing Process Development

C h a r a c t e r i s a t i o n

— Elucidation of Structure and other Characteristics

— Impurities

C o n t r o l o f A c t i v e S u b s t a n c e

— Specification

— Analytical Procedures

— Validation of Analytical Procedures

— Batch Analyses

— Justification of Specification

R e f e r e n c e S t a n d a r d s o r M a t e r i a l s

C o n t a i n e r C l o s u r e S y s t e m

S t a b i l i t y

— Stability Summary and Conclusions

— Post-approval Stability Protocol and Stability Commitment

— Stability Data

— Finished Medicinal Product

D e s c r i p t i o n a n d C o m p o s i t i o n o f t h e M e d i c i n a l P r o d u c t

P h a r m a c e u t i c a l D e v e l o p m e n t

— Components of the Medicinal Product

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— Active Substance

— Excipients

— Medicinal Product

— Formulation Development

— Overages

— Physicochemical and Biological Properties

— Manufacturing Process Development

— Container Closure System

— Microbiological Attributes

— Compatibility

M a n u f a c t u r e

— Manufacturer(s)

— Batch Formula

— Description of Manufacturing Process and Process Controls

— Controls of Critical Steps and Intermediates

— Process Validation and/or Evaluation

C o n t r o l o f E x c i p i e n t s

— Specifications

— Analytical Procedures

— Validation of Analytical Procedures

— Justification of Specifications

— Excipients of Human or Animal Origin

— Novel Excipients

C o n t r o l o f F i n i s h e d M e d i c i n a l P r o d u c t

— Specification(s)

— Analytical Procedures

— Validation of Analytical Procedures

— Batch Analyses

— Characterisation of Impurities

— Justification of Specification(s)

R e f e r e n c e S t a n d a r d s o r M a t e r i a l s

C o n t a i n e r C l o s u r e S y s t e m

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S t a b i l i t y

— Stability Summary and Conclusion

— Post-approval Stability Protocol and Stability Commitment

— Stability Data

— Appendices

— Facilities and Equipment (Biological Medicinal Products only)

— Adventitious Agents Safety Evaluation

— Excipients

— European Community Additional Information

— Process Validation Scheme for the Medicinal Product

— Medical Device

— Certificate(s) of Suitability

— Medicinal products containing or using in the manufacturing process materials of

animal and/or human origin (TSE procedure)

— Literature References

3.2. Content: basic principles and requirements

(1) The chemical, pharmaceutical and biological data that shall be provided shall include

for the active substance(s) and for the finished medicinal product all of relevant

information on: the development, the manufacturing process, the characterisation and

properties, the quality control operations and requirements, the stability as well as a

description of the composition and presentation of the finished medicinal product.

(2) Two main sets of information shall be provided, dealing with the active substance(s)

and with the finished medicinal product, respectively.

(3) This Module shall in addition supply detailed information on the starting and raw

materials used during the manufacturing operations of the active substance(s) and on the

excipients incorporated in the formulation of the finished medicinal product.

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(4) All the procedures and methods used for manufacturing and controlling the active

substance and the finished medicinal product shall be described in sufficient details to

enable them to be repeated in control tests, carried out at the request of the competent

authority. All test procedures shall correspond to the state of scientific progress at the

time and shall be validated. Results of the validation studies shall be provided. In the

case of test procedures included in the European Pharmacopoeia, this description shall

be replaced by the appropriate detailed reference to the monograph(s) and general

chapter(s).

(5) The monographs of the European Pharmacopoeia shall be applicable to all substances,

preparations and pharmaceutical forms appearing in it. In respect of other substances,

each Member State may require observance of its own national pharmacopoeia.

However, where a material in the European Pharmacopoeia or in the pharmacopoeia of

a Member State has been prepared by a method liable to leave impurities not controlled

in the pharmacopoeia monograph, these impurities and their maximum tolerance limits

must be declared and a suitable test procedure must be described. In cases where a

specification contained in a monograph of the European Pharmacopoeia or in the

national pharmacopoeia of a Member State might be insufficient to ensure the quality of

the substance, the competent authorities may request more appropriate specifications

from the marketing authorisation holder. The competent authorities shall inform the

authorities responsible for the pharmacopoeia in question. The marketing authorisation

holder shall provide the authorities of that pharmacopoeia with the details of the alleged

insufficiency and the additional specifications applied.

In the case of analytical procedures included in the European Pharmacopoeia, this

description shall be replaced in each relevant section by the appropriate detailed

reference to the monograph(s) and general chapter(s).

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(6) In case where starting and raw materials, active substance(s) or excipient(s) are

described neither in the European Pharmacopoeia nor in the pharmacopoeia of a

Member State, compliance with the monograph of a third country pharmacopoeia can

be accepted. In such cases, the applicant shall submit a copy of the monograph

accompanied by the validation of the analytical procedures contained in the monograph

and by a translation where appropriate.

(7) Where the active substance and/or a raw and starting material or excipient(s) are the

subject of a monograph of the European Pharmacopoeia, the applicant can apply for a

certificate of suitability that, where granted by the European Directorate for the Quality

of Medicines, shall be presented in the relevant section of this Module. Those

certificates of suitability of the monograph of the European Pharmacopoeia are deemed

to replace the relevant data of the corresponding sections described in this Module. The

manufacturer shall give the assurance in writing to the applicant that the manufacturing

process has not been modified since the granting of the certificate of suitability by the

European Directorate for the Quality of Medicines.

(8) For a well-defined active substance, the active substance manufacturer or the applicant

may arrange for the

(i) detailed description of the manufacturing process,

(ii) quality control during manufacture, and

(iii) process validation

to be supplied in a separate document directly to the competent authorities by the

manufacturer of the active substance as an Active Substance Master File.

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In this case, the manufacturer shall, however, provide the applicant with all of the data,

which may be necessary for the latter to take responsibility for the medicinal product.

The manufacturer shall confirm in writing to the applicant that he shall ensure batch to

batch consistency and not modify the manufacturing process or specifications without

informing the applicant. Documents and particulars supporting the application for such

a change shall be supplied to the competent authorities; these documents and particulars

will be also supplied to the applicant when they concern the open part of the active

substance master file.

(9) Specific measures concerning the prevention of the transmission of animal spongiform

encephalopathies (materials from ruminant origin): at each step of the manufacturing

process, the applicant must demonstrate the compliance of the materials used with the

Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform

Encephalopathy Agents via Medicinal Products and its updates, published by the

Commission in the Official Journal of the European Union. Demonstration of

compliance with the said Note for Guidance can be done by submitting either,

preferably a certificate of suitability to the relevant monograph of the European

Pharmacopoeia that has been granted by the European Directorate for the Quality of

Medicines or by the supply of scientific data to substantiate this compliance.

(10) For adventitious agents, information assessing the risk with respect to potential

contamination with adventitious agents, whether they are non-viral or viral, as laid

down in relevant guidelines as well as in relevant general monograph and general

chapter of the European Pharmacopoeia, shall be provided.

(11) Any special apparatus and equipment, which may be used at any stage of the

manufacturing process and control operations of the medicinal product, shall be

described in adequate details.

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(12) Where, in accordance with the second subparagraph of Article 1(8) or the second

subparagraph of Article 1(9) of Regulation (EU) 2017/745 of the European Parliament

and of the Council (56), a product is governed by this Directive, the marketing

authorisation dossier shall include, where available, the results of the assessment of the

conformity of the device part with the relevant general safety and performance

requirements set out in Annex I to that Regulation contained in the manufacturer's EU

declaration of conformity or the relevant certificate issued by a notified body allowing

the manufacturer to affix a CE marking to the medical device.

If the dossier does not include the results of the conformity assessment referred to in the

first subparagraph and where for the conformity assessment of the device, if used

separately, the involvement of a notified body is required in accordance with

Regulation (EU) 2017/745, the authority shall require the applicant to provide an

opinion on the conformity of the device part with the relevant general safety and

performance requirements set out in Annex I to that Regulation issued by a notified

body designated in accordance with that Regulation for the type of device in question.

3.2.1

Active substance(s)

3.2.1.1.

G e n e r a l i n f o r m a t i o n a n d i n f o r m a t i o n r e l a t e d t o t h e s t a r t i n g

a n d r a w m a t e r i a l s

Information on the nomenclature of the active substance shall be provided,

including recommended International Non-proprietary Name (INN), European

Pharmacopoeia name if relevant, chemical name(s).

The structural formula, including relative and absolute stereo-chemistry, the

molecular formula, and the relative molecular mass shall be provided. For

biotechnological medicinal products if appropriate, the schematic amino acid

sequence and relative molecular mass shall be provided.

Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical
devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No
1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC (OJ L 117, 5.5.2017, p. 1)

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A list shall be provided of physicochemical and other relevant properties of the

active substance, including biological activity for biological medicinal products.

For the purposes of this Annex, starting materials shall mean all the materials

from which the active substance is manufactured or extracted.

For biological medicinal products, starting materials shall mean any substance of

biological origin such as micro-organisms, organs and tissues of either plant or

animal origin, cells or fluids (including blood or plasma) of human or animal

origin, and biotechnological cell constructs (cell substrates, whether they are

recombinant or not, including primary cells).

A biological medicinal product is a product, the active substance of which is a

biological substance. A biological substance is a substance that is produced by or

extracted from a biological source and that needs for its characterisation and the

determination of its quality a combination of physico-chemical-biological testing,

together with the production process and its control. The following shall be

considered as biological medicinal products: immunological medicinal products

and medicinal products derived from human blood and human plasma as defined,

respectively in paragraphs (4) and (10) of Article 1; medicinal products falling

within the scope of Part A of the Annex to Regulation (EEC) No 2309/93;

advanced therapy medicinal products as defined in Part IV of this Annex.

Any other substances used for manufacturing or extracting the active substance(s)

but from which this active substance is not directly derived, such as reagents,

culture media, foetal calf serum, additives, and buffers involved in

chromatography, etc. are known as raw materials.

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3.2.1.2.

M a n u f a c t u r i n g p r o c e s s o f t h e a c t i v e s u b s t a n c e ( s )

The description of the active substance manufacturing process represents the

applicant's commitment for the manufacture of the active substance. To

adequately describe the manufacturing process and process controls, appropriate

information as laid down in guidelines published by the Agency shall be provided.

All materials needed in order to manufacture the active substance(s) shall be

listed, identifying where each material is used in the process. Information on the

quality and control of these materials shall be provided. Information

demonstrating that materials meet standards appropriate for their intended use

shall be provided.

Raw materials shall be listed and their quality and controls shall also be

documented.

The name, address, and responsibility of each manufacturer, including contractors,

and each proposed production site or facility involved in manufacturing and

testing shall be provided.

c) For biological medicinal products, the following additional requirements shall

apply.

The origin and history of starting materials shall be described and documented.

Regarding the specific measures for the prevention of the Transmission of animal

Spongiform Encephalopathies, the applicant must demonstrate that the active

substance complies with the Note for Guidance on Minimising the Risk of

Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products

and its updates, published by the Commission in the Official Journal of the

European Union.

When cell banks are used, the cell characteristics shall be shown to have remained

unchanged at the passage level used for the production and beyond.

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Seed materials, cell banks, pools of serum or plasma and other materials of

biological origin and, whenever possible, the materials from which they are

derived shall be tested for adventitious agents.

If the presence of potentially pathogenic adventitious agents is inevitable, the

corresponding material shall be used only when further processing ensures their

elimination and/or inactivation, and this shall be validated.

Whenever possible, vaccine production shall be based on a seed lot system and on

established cell banks. For bacterial and viral vaccines, the characteristics of the

infectious agent shall be demonstrated on the seed. In addition, for live vaccines,

the stability of the attenuation characteristics shall be demonstrated on the seed; if

this proof is not sufficient, the attenuation characteristics shall also be

demonstrated at the production stage.

For medicinal products derived from human blood or plasma, the origin and the

criteria and procedures for collection, transportation and storage of the starting

material shall be described and documented in accordance with provisions laid

down in Part III of this Annex.

The manufacturing facilities and equipment shall be described.

Tests and acceptance criteria carried out at every critical step, information on the

quality and control of intermediates and process validation and/or evaluation

studies shall be provided as appropriate.

If the presence of potentially pathogenic adventitious agents is inevitable, the

correspondent material shall be used only when further processing ensures their

elimination and/or inactivation and this shall be validated in the section dealing

with viral safety evaluation.

A description and discussion of the significant changes made to the manufacturing

process during development and/or manufacturing site of the active substance

shall be provided.

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3.2.1.3.

C h a r a c t e r i s a t i o n o f t h e a c t i v e s u b s t a n c e ( s )

Data highlighting the structure and other characteristics of the active substance(s) shall

be provided.

Confirmation of the structure of the active substance(s) based on any physico-chemical

and/or immuno-chemical and/or biological methods, as well as information on

impurities shall be provided.

3.2.1.4.

C o n t r o l o f a c t i v e s u b s t a n c e ( s )

Detailed information on the specifications used for routine control of active

substance(s), justification for the choice of these specifications, methods of analysis and

their validation shall be provided.

The results of control carried out on individual batches manufactured during

development shall be presented.

3.2.1.5.

R e f e r e n c e s t a n d a r d s o r m a t e r i a l s

Reference preparations and standards shall be identified and described in detail. Where

relevant, chemical and biological reference material of the European Pharmacopoeia

shall be used.

3.2.1.6

C o n t a i n e r a n d c l o s u r e s y s t e m o f t h e a c t i v e s u b s t a n c e

A description of the container and the closure system(s) and their specifications shall be

provided.

3.2.1.7.

S t a b i l i t y o f t h e a c t i v e s u b s t a n c e (s)

The type s of studies conducted, protocols used, and the results of the studies

shall be summarised

Detailed results of the stability studies, including information on the analytical

procedures used to generate the data and validation of these procedures shall be

presented in an appropriate format

The post authorisation stability protocol and stability commitment shall be

provided

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3.2.2 Finished medicinal product

3.2.2.1

D e s c r i p t i o n a n d c o m p o s i t i o n o f t h e f i n i s h e d m e d i c i n a l

p r o d u c t

A description of the finished medicinal product and its composition shall be provided.

The information shall include the description of the pharmaceutical form and

composition with all the constituents of the finished medicinal product, their amount on

a per-unit basis, the function of the constituents of:

— the active substance(s),

— the constituent(s) of the excipients, whatever their nature or the quantity used,

including colouring matter, preservatives, adjuvants, stabilisers, thickeners,

emulsifiers, flavouring and aromatic substances, etc.,

— the constituen’ts, intended to be ingested or otherwise administered to the patient,

of the outer covering of the medicinal products (hard capsules, soft capsules,

rectal capsules, coated tablets, films-coated tablets, etc.),

— these particulars shall be supplemented by any relevant data concerning the type

of container and, where appropriate, its manner of closure, together with details of

devices with which the medicinal product will be used or administered and which

will be delivered with the medicinal product.

The ‘usual terminology’, to be used in describing the constituents of medicinal products,

shall mean, notwithstanding the application of the other provisions in Article 8 (3) (c):

— in respect of substances which appear in the European Pharmacopoeia or, failing

this, in the national pharmacopoeia of one of the Member States, the main title at

the head of the monograph in question, with reference to the pharmacopoeia

concerned,

— in respect of other substances, the international non-proprietary name (INN)

recommended by the World Health Organisation, or, failing this, the exact

scientific designation; substances not having an international non-proprietary

name or an exact scientific designation shall be described by a statement of how

and from what they were prepared, supplemented, where appropriate, by any other

relevant details,

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— in respect of colouring matter, designation by the ‘E’ code assigned to them in

Council Directive 78/25/EEC of 12 December 1977 on the approximation of the

rules of the Member States concerning the colouring matters authorised for use in

medicinal products (57) and/or European Parliament and Council Directive

94/36/EC of 30 June 1994 on colours for use in foodstuffs (58).

In order to give the ‘quantitative composition’ of the active substance(s) of the finished

medicinal products, it is necessary, depending on the pharmaceutical form concerned, to

specify the mass, or the number of units of biological activity, either per dosage-unit or

per unit of mass or volume, of each active substance.

Active substances present in the form of compounds or derivatives shall be designated

quantitatively by their total mass, and if necessary or relevant, by the mass of active

entity or entities of the molecule.

For medicinal products containing an active substance, which is the subject of an

application for marketing authorisation in any Member State for the first time, the

quantitative statement of an active substance, which is a salt or hydrate shall be

systematically expressed in terms of the mass of the active entity or entities in the

molecule. All subsequently authorised medicinal products in the Member States shall

have their quantitative composition stated in the same way for the same active

substance.

Units of biological activity shall be used for substances, which cannot be defined

molecularly. Where an International Unit of biological activity has been defined by the

World Health Organisation, this shall be used. Where no International Unit has been

defined, the units of biological activity shall be expressed in such a way as to provide

unambiguous information on the activity of the substances by using where applicable

the European Pharmacopoeia Units.

OJ L 11, 14.1.1978, p. 18

OJ L 237, 10.9.1994, p. 13

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3.2.2.2.

P h a r m a c e u t i c a l d e v e l o p m e n t

This chapter shall be devoted to information on the development studies conducted to

establish that the dosage form, the formulation, manufacturing process, container

closure system, microbiological attributes and usage instructions are appropriate for the

intended use specified in the marketing authorisation application dossier.

The studies described in this chapter are distinct from routine control tests conducted

according to specifications. Critical parameters of the formulation and process attributes

that can influence batch reproducibility, medicinal product performance and medicinal

product quality shall be identified and described. Additional supportive data, where

appropriate, shall be referenced to the relevant chapters of Module 4 (Non Clinical

Study Reports) and Module 5 (Clinical Study Reports) of the marketing authorisation

application dossier.

a) The compatibility of the active substance with excipients as well as key

physicochemical characteristics of the active substance that can influence the

performance of the finished product or the compatibility of different active

substances with each other in the case of combination products, shall be

documented.

b) The choice of excipients, in particular relative to their respective functions and

concentration shall be documented.

c) A description of the development of the finished product shall be provided, taking

into consideration the proposed route of administration and usage.

d) Any overages in the formulation(s) shall be warranted.

e) As far as the physiochemical and biological properties are concerned, any

parameter relevant to the performance of finished product shall be addressed and

documented.

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The selection and optimisation of the manufacturing process as well as differences

between the manufacturing process(es) used to produce pivotal clinical batches

and the process used for manufacturing the proposed finished medicinal product

shall be provided.

g) The suitability of the container and closure system used for the storage, shipping

and use of the finished product shall be documented. A possible interaction

between medicinal product and container may need to be considered.

h) The microbiological attributes of the dosage form in relation with non-sterile and

sterile products shall be in accordance with and documented as prescribed in the

European Pharmacopoeia.

In order to provide appropriate and supportive information for the labelling the

compatibility of the finished product with reconstitution diluent(s) or dosage

devices shall be documented

3.2.2.3.

M a n u f a c t u r i n g p r o c e s s o f t h e f i n i s h e d m e d i c i n a l p r o

d u c t

a) The description of the manufacturing method accompanying the application for

Marketing Authorisation pursuant to Article 8 (3) (d), shall be drafted in such a

way as to give an adequate synopsis of the nature of the operations employed.

For this purpose it shall include at least:

— mention of the various stages of manufacture including process controls and

corresponding acceptance criteria, so that an assessment can be made of

whether the processes employed in producing the pharmaceutical form might

have produced an adverse change in the constituents,

— in the case of continuous manufacture, full details concerning precautions

taken to ensure the homogeneity of the finished product,

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— experimental studies validating the manufacturing process, where a non-

standard method of manufacture is used or where it is critical for the product,

— for sterile medicinal products, details of the sterilisation processes and/or

aseptic procedures used,

— a detailed batch formula.

The name, address, and responsibility of each manufacturer, including contractors,

and each proposed production site or facility involved in manufacturing and

testing shall be provided.

b) Particulars relating to the product control tests that may be carried out at an

intermediate stage of the manufacturing process, with a view to ensuring the

consistency of the production process shall be included.

These tests are essential for checking the conformity of the medicinal product

with the formula when, exceptionally, an applicant proposes an analytical method

for testing the finished product which does not include the assay of all the active

substances (or of all the excipient constituents subject to the same requirements as

the active substances).

The same applies where the quality control of the finished product depends on in-

process control tests, particularly if the medicinal product is essentially defined by

its method of preparation.

c) Description, documentation, and results of the validation studies for critical steps

or critical assays used in the manufacturing process shall be provided.

3.2.2.4.

C o n t r o l o f e x c i p i e n t s

a) All the materials needed in order to manufacture the excipient(s) shall be listed

identifying where each material is used in the process. Information on the quality

and control of these materials shall be provided. Information demonstrating that

materials meet standards appropriate for their intended use shall be provided.

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Colouring matter shall, in all cases, satisfy the requirements of Directives

78/25/EEC and/or 94/36/EC. In addition, colouring matter shall meet purity

criteria as laid down in Directive 95/45/EC, as amended.

b) For each excipient, the specifications and their justifications shall be detailed. The

analytical procedures shall be described and duly validated.

c) Specific attention shall be paid to excipients of human or animal origin.

Regarding the specific measures for the prevention of the Transmission of animal

Spongiform Encephalopathies, the applicant must demonstrate also for excipients

that the medicinal product is manufactured in accordance with the Note for

Guidance on Minimising the Risk of Transmitting Animal Spongiform

Encephalopathy Agents via Medicinal Products and its updates, published by the

Commission in the Official Journal of the European Union.

Demonstration of compliance with the aforementioned Note for Guidance can be

done by submitting either preferably a certificate of suitability to the relevant

monograph on Transmissible Spongiform Encephalopathies of the European

Pharmacopoeia, or by the supply of scientific data to substantiate this compliance.

d) Novel excipients:

For excipient(s) used for the first time in a medicinal product or by a new route of

administration, full details of manufacture, characterisation, and controls, with

cross references to supporting safety data, both non-clinical and clinical, shall be

provided according to the active substance format previously described.

A document containing the detailed chemical, pharmaceutical and biological

information shall be presented. This information shall be formatted in the same

order as the chapter devoted to Active Substance(s) of Module 3.

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Information on novel excipient(s) may be presented as a stand-alone document

following the format described in the former paragraphs. Where the applicant

differs from the novel excipient manufacturer the said stand-alone document shall

be made available to the applicant for submission to the competent authority.

Additional information on toxicity studies with the novel excipient shall be

provided in Module 4 of the dossier.

Clinical studies shall be provided in Module 5.

3.2.2.5.

C o n t r o l o f t h e f i n i s h e d m e d i c i n a l p r o d u c t

For the control of the finished medicinal product, a batch of a medicinal product is an

entity which comprises all the units of a pharmaceutical form which are made from the

same initial quantity of material and have undergone the same series of manufacturing

and/or sterilisation operations or, in the case of a continuous production process, all the

units manufactured in a given period of time.

Unless there is appropriate justification, the maximum acceptable deviation in the active

substance content of the finished product shall not exceed ± 5 % at the time of

manufacture.

Detailed information on the specifications, (release and shelf life) justification for their

choice, methods of analysis and their validation shall be provided.

3.2.2.6.

R e f e r e n c e s t a n d a r d s o r m a t e r i a l s

Reference preparations and standards used for testing of the finished medicinal product

shall be identified and described in detail, if not previously provided in the section

related to the active substance.

3.2.2.7.

C o n t a i n e r a n d c l o s u r e o f t h e f i n i s h e d m e d i c i n a l p r o d u c t

A description of the container and the closure system(s) including the identity of each

immediate packaging material and their specifications shall be provided. The

specifications shall include description and identification. Non-pharmacopoeial methods

(with validation) shall be included where appropriate.

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For non-functional outer packaging materials only a brief description shall be provided.

For functional outer packaging materials additional information shall be provided.

3.2.2.8.

S t a b i l i t y o f t h e f i n i s h e d m e d i c i n a l p r o d u c t

a) The types of studies conducted, protocols used, and the results of the studies shall

be summarised;

b) Detailed results of the stability studies, including information on the analytical

procedures used to generate the data and validation of these procedures shall be

presented in an appropriate format; in case of vaccines, information on cumulative

stability shall be provided where appropriate;

The post authorisation stability protocol and stability commitment shall be

provided.

MODULE 4: NON-CLINICAL REPORTS

4.1. Format and Presentation

The general outline of Module 4 is as follows:

— Table of contents

— Study reports

— Pharmacology

— Primary Pharmaco-dynamics

— Secondary Pharmaco-dynamics

— Safety Pharmacology

— Pharmaco-dynamic Interactions

— Pharmaco-kinetics

— Analytical Methods and Validation Reports

— Absorption

— Distribution

— Metabolism

— Excretion

— Pharmaco-kinetic Interactions (non-clinical)

— Other Pharmaco-kinetic Studies

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— Toxicology

— Single-Dose Toxicity

— Repeat-Dose Toxicity

— Genotoxicity

— In vitro

— In vivo (including supportive toxico-kinetics evaluations)

— Carcinogenicity

— Long-term studies

— Short- or medium-term studies

— Other studies

— Reproductive and Developmental Toxicity

— Fertility and early embryonic development

— Embryo-fetal development

— Prenatal and postnatal development

— Studies in which the offspring (juvenile animals) are dosed and/or further

evaluated

— Local Tolerance

— Other Toxicity Studies

— Antigenicity

— Immuno-toxicity

— Mechanistic studies

— Dependence

— Metabolites

— Impurities

— Other

— Literature references

4.2. Content: basic principles and requirements

Special attention shall be paid to the following selected elements.

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(1) The pharmacological and toxicological tests must show:

a) the potential toxicity of the product and any dangerous or undesirable toxic effects

that may occur under the proposed conditions of use in human beings; these

should be evaluated in relation to the pathological condition concerned;

b) the pharmacological properties of the product, in both qualitative and quantitative

relationship to the proposed use in human beings. All results must be reliable and

of general applicability. Whenever appropriate, mathematical and statistical

procedures shall be used in designing the experimental methods and in evaluating

the results.

Additionally, it is necessary for clinicians to be given information about the

therapeutic and toxicological potential of the product.

(2) For biological medicinal products such as immunological medicinal products and

medicinal products derived from human blood or plasma, the requirements of this

Module may have to be adapted for individual products; therefore the testing

program carried out shall be justified by the applicant.

In establishing the testing program, the following shall be taken into

consideration:

all tests requiring repeated administration of the product shall be designed to take

account of the possible induction of, and interference by, antibodies;

examination of reproductive function, of embryo/foetal and peri-natal toxicity, of

mutagenic potential and of carcinogenic potential shall be considered. Where

constituents other than the active substance(s) are incriminated, validation of their

removal may replace the study.

(3) The toxicology and pharmaco-kinetics of an excipient used for the first time in the

pharmaceutical field shall be investigated.

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(4) Where there is a possibility of significant degradation during storage of the

medicinal product, the toxicology of degradation products must be considered.

4.2.1. Pharmacology

Pharmacology study shall follow two distinct lines of approach.

— Firstly, the actions relating to the proposed therapeutic use shall be adequately

investigated and described. Where possible, recognised and validated assays, both in

vivo and in vitro, shall be used. Novel experimental techniques must be described in

such detail as to allow them to be reproduced. The results shall be expressed in

quantitative terms using, for example, dose-effect curves, time-effect curves, etc.

Wherever possible, comparisons shall be made with data relating to a substance or

substances with a similar therapeutic action.

— Secondly, the applicant shall investigate the potential undesirable pharmaco-dynamic

effects of the substance on physiological functions. These investigations shall be

performed at exposures in the anticipated therapeutic range and above. The

experimental techniques, unless they are standard procedures, must be described in such

detail as to allow them to be reproduced, and the investigator must establish their

validity. Any suspected modification of responses resulting from repeated

administration of the substance shall be investigated.

For the pharmaco-dynamic medicinal product interaction, tests on combinations of

active substances may be prompted either by pharmacological premises or by

indications of therapeutic effect. In the first case, the pharmaco-dynamic study shall

demonstrate those interactions, which might make the combination of value in

therapeutic use. In the second case, where scientific justification for the combination is

sought through therapeutic experimentation, the investigation shall determine whether

the effects expected from the combination can be demonstrated in animals, and the

importance of any collateral effects shall at least be investigated.

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4.2.2. Pharmaco-kinetics

Pharmaco-kinetics means the study of the fate of the active substance, and its metabolites,

within the organism, and covers the study of the absorption, distribution, metabolism (bio-

transformation) and excretion of these substances.

The study of these different phases may be carried mainly by means of physical, chemical

or possibly by biological methods, and by observation of the actual pharmaco-dynamic

activity of the substance itself.

Information on distribution and elimination shall be necessary in all cases where such data

are indispensable to determine the dosage for humans, and in respect of chemo-therapeutic

substances (antibiotics, etc.) and substances whose use depends on their non-pharmaco-

dynamic effects (e.g. numerous diagnostic agents, etc.).

In vitro studies also can be carried out with the advantage of using human material for

comparison with animal material (i.e. protein binding, metabolism, drug-drug interaction).

Pharmaco-kinetic investigation of all pharmacologically active substances is necessary. In

the case of new combinations of known substances, which have been investigated in

accordance with the provisions of this Directive, pharmaco-kinetic studies may not be

required, if the toxicity tests and therapeutic experimentation justify their omission.

The pharmaco-kinetic program shall be design to allow comparison and extrapolation

between animal and human.

4.2.3. Toxicology

a) Single-dose toxicity

A single-dose toxicity test shall mean a qualitative and quantitative study of the toxic

reactions, which may result from a single administration of the active substance or

substances contained in the medicinal product, in the proportions and physico-

chemical state in which they are present in the actual product.

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The single-dose toxicity test must be carried out in accordance with the relevant

guidelines published by the Agency.

b) Repeat-dose toxicity

Repeated dose toxicity tests are intended to reveal any physiological and/or anatomo-

pathological changes induced by repeated administration of the active substance or

combination of active substances under examination, and to determine how these

changes are related to dosage.

Generally, it is desirable that two tests be performed: one short term, lasting two to

four weeks, the other long-term. The duration of the latter shall depend on the

conditions of clinical use. Its purpose is to describe potential adverse effects to which

attention should be paid in clinical studies. The duration is defined in the relevant

guidelines published by the Agency.

c) Geno-toxicity

The purposes of the study of mutagenic and clastogenic potential is to reveal the

changes which a substance may cause in the genetic material of individuals or cells.

Mutagenic substances may present a hazard to health since exposure to a mutagen

carries the risk of inducing germ-line mutation, with the possibility of inherited

disorders, and the risk of somatic mutations including those leading to cancer. These

studies are obligatory for any new substance.

d) Carcino-genicity

Tests to reveal carcinogenic effects shall normally be required:

These studies shall be performed for any medicinal product whose expected

clinical use is for a prolonged period of a patient's life, either continuously or

repeatedly in an intermittent manner.

These studies are recommended for some medicinal products if there is

concern about their carcinogenic potential, e.g. from product of the same class

or similar structure, or from evidence in repeated dose toxicity studies.

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Studies with unequivocally geno-toxic compounds are not needed, as they are

presumed to be trans-species carcinogens, implying a hazard to humans. If

such a medicinal product is intended to be administered chronically to humans

a chronic study may be necessary to detect early tumorigenic effects.

e) Reproductive and developmental toxicity

Investigation of possible impairment of male or female reproductive function as well

as harmful effects on progeny shall be performed by appropriate tests.

These tests comprise studies of effect on adult male or female reproductive function,

studies of the toxic and teratogenic effects at all stages of development from

conception to sexual maturity as well as latent effects, when the medicinal product

under investigation has been administered to the female during pregnancy.

Omission of these tests must be adequately justified.

Depending on the indicated use of the medicinal product, additional studies

addressing development when administering the medicinal product of the offspring

may be warranted.

Embryo/foetal toxicity studies shall normally be conducted on two mammalian

species, one of which shall be other than a rodent. Peri- and postnatal studies shall be

conducted in at least one species. If the metabolism of a medicinal product in

particular species is known to be similar to that in man, it is desirable to include this

species. It is also desirable that one of the species is the same as in the repeated dose

toxicity studies.

The state of scientific knowledge at the time when the application is lodged shall be

taken into account when determining the study design.

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Local tolerance

The purpose of local tolerance studies is to ascertain whether medicinal products

(both active substances and excipients) are tolerated at sites in the body, which may

come into contact with the medicinal product as a result of its administration in

clinical use. The testing strategy shall be such that any mechanical effects of

administration or purely physico-chemical actions of the product can be

distinguished from toxicological or pharmaco-dynamic ones.

Local tolerance testing shall be conducted with the preparation being developed for

human use, using the vehicle and/or excipients in treating the control group(s).

Positive controls/reference substances shall be included where necessary.

The design of local tolerance tests (choice of species, duration, frequency and route

of administration, doses) will depend upon the problem to be investigated and the

proposed conditions of administration in clinical use. Reversibility of local lesions

shall be performed where relevant.

Studies in animals can be substituted by validated in vitro tests provided that the test

results are of comparable quality and usefulness for the purpose of safety evaluation.

For chemicals applied to the skin (e.g. dermal, rectal, vaginal) the sensitising

potential shall be evaluated in at least one of the test systems currently available (the

guinea pig assay or the local lymph node assay).

MODULE 5: CLINICAL STUDY REPORTS

5.1. Format and Presentation

The general outline of Module 5 is as follows:

— Table of contents for clinical study reports

— Tabular listing of all clinical studies

— Clinical study reports

— Reports of Bio-pharmaceutical Studies

— Bio-availability Study Reports

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— Comparative Bio-availability and Bio-equivalence Study Reports

— In vitro — In vivo Correlation Study Report

— Reports of Bio-analytical and Analytical Methods

— Reports of Studies Pertinent to Pharmaco-kinetics Using Human Bio-materials

— Plasma Protein Binding Study Reports

— Reports of Hepatic Metabolism and Interaction Studies

— Reports of Studies Using Other Human Bio-materials

— Reports of Human Pharmaco-kinetic Studies

— Healthy subjects Pharmaco-kinetics and Initial Tolerability Study Reports

— Patient Pharmaco-kinetics and Initial Tolerability Study Reports

— Intrinsic Factor Pharmaco-kinetics Study Reports

— Extrinsic Factor Pharmaco-kinetics Study Reports

— Population Pharmaco-kinetics Study Reports

— Reports of Human Pharmaco-dynamic Studies

— Healthy Subject Pharmaco-dynamic and Pharmaco-kinetics/Pharmaco-dynamic

Study Reports

— Patient Pharmaco-dynamic and Pharmaco-kinetics/Pharmaco-dynamic Studies Study

Reports

— Reports of Efficacy and Safety Studies

— Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication

— Study Reports of Uncontrolled Clinical Studies

— Reports of Analyses of Data from More than One Study including any formal

integrated analyses, meta-analyses and bridging analyses

— Other Study Reports

— Reports of Post-marketing Experience

— Literature references

5.2. Content: basic principles and requirements

Special attention shall be paid to the following selected elements.

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a) The clinical particulars to be provided pursuant to Articles 8 (3) (i) and 10 (1) must

enable a sufficiently well-founded and scientifically valid opinion to be formed as to

whether the medicinal product satisfies the criteria governing the granting of a

marketing authorisation. Consequently, an essential requirement is that the results of all

clinical trials should be communicated, both favourable and unfavourable.

b) Clinical trials must always be preceded by adequate pharmacological and toxicological

tests, carried out on animals in accordance with the requirements of Module 4 of this

Annex. The investigator must acquaint himself with the conclusions drawn from the

pharmacological and toxicological studies and hence the applicant must provide him at

least with the investigator's brochure, consisting of all the relevant information known

prior to the onset of a clinical trial including chemical, pharmaceutical and biological

data, toxicological, pharmaco-kinetic and pharmaco-dynamic data in animals and the

results of earlier clinical trials, with adequate data to justify the nature, scale and

duration of the proposed trial; the complete pharmacological and toxicological reports

shall be provided on request. For materials of human or animal origin, all available

means shall be employed to ensure safety from transmission of infectious agents prior to

the commencement of the trial.

c) Marketing authorisation holders must arrange for essential clinical trial documents

(including case report forms) other than subject's medical files, to be kept by the owners

of the data:

— for at least 15 years after completion or discontinuation of the trial,

— or for at least two years after the granting of the last marketing authorisation in the

European Community and when there are no pending or contemplated marketing

applications in the European Community,

— or for at least two years after formal discontinuation of clinical development of the

investigational product.

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Subject's medical files should be retained in accordance with applicable legislation and

in accordance with the maximum period of time permitted by the hospital, institution or

private practice.

The documents can be retained for a longer period, however, if required by the

applicable regulatory requirements or by agreement with the sponsor. It is the

responsibility of the sponsor to inform the hospital, institution or practice as to when

these documents no longer need to be retained.

The sponsor or other owner of the data shall retain all other documentation pertaining to

the trial as long as the product is authorised. This documentation shall include: the

protocol including the rationale, objectives and statistical design and methodology of

the trial, with conditions under which it is performed and managed, and details of the

investigational product, the reference medicinal product and/or the placebo used;

standard operating procedures; all written opinions on the protocol and procedures; the

investigator's brochure; case report forms on each trial subject; final report; audit

certificate(s), if available. The final report shall be retained by the sponsor or

subsequent owner, for five years after the medicinal product is no longer authorised.

In addition for trials conducted within the European Community, the marketing

authorisation holder shall make any additional arrangements for archiving of

documentation in accordance with the provisions of Directive 2001/20/EC and

implementing detailed guidelines.

Any change of ownership of the data shall be documented.

All data and documents shall be made available if requested by relevant authorities.

d) The particulars of each clinical trial must contain sufficient detail to allow an objective

judgement to be made:

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— the protocol, including the rationale, objectives and statistical design and

methodology of the trial, with conditions under which it is performed and

managed, and details of the investigational medicinal product used

— audit certificate(s), if available

— the list of investigator(s), and each investigator shall give his name, address,

appointments, qualifications and clinical duties, state where the trial was carried

out and assemble the information in respect of each patient individually, including

case report forms on each trial subject

— final report signed by the investigator and for multi-centre trials, by all the

investigators or the co-ordinating (principal) investigator.

e) The particulars of clinical trials referred to above shall be forwarded to the competent

authorities. However, in agreement with the competent authorities, the applicant may

omit part of this information. Complete documentation shall be provided forthwith upon

request.

The investigator shall, in his conclusions on the experimental evidence, express an

opinion on the safety of the product under normal conditions of use, its tolerance, its

efficacy and any useful information relating to indications and contra-indications,

dosage and average duration of treatment as well as any special precautions to be taken

during treatment and the clinical symptoms of over dosage. In reporting the results of a

multi-centre study, the principal investigator shall, in his conclusions, express an

opinion on the safety and efficacy of the investigational medicinal product on behalf of

all centres.

The clinical observations shall be summarised for each trial indicating:

1) the number and sex of subjects treated;

2) the selection and age-distribution of the groups of patients being investigated and

the comparative tests;

3) the number of patients withdrawn prematurely from the trials and the reasons for

such withdrawal;

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4) where controlled trials were carried out under the above conditions, whether the

control group:

— received no treatment

— received a placebo

— received another medicinal product of known effect

— received treatment other than therapy using medicinal products

5) the frequency of observed adverse reactions;

6) details concerning patients who may be at increased risk, e.g. elderly people,

children, women during pregnancy or menstruation, or whose physiological or

pathological condition requires special consideration;

7) parameters or evaluation criteria of efficacy and the results in terms of these

parameters;

8) a statistical evaluation of the results when this is called for by the design of the

trials and the variable factors involved.

g) In addition, the investigator shall always indicate his observations on:

1) any signs of habituation, addiction or difficulty in weaning patients from the

medicinal product;

2) any interactions that have been observed with other medicinal products

administered concomitantly;

3) the criteria determining exclusion of certain patients from the trials;

4) any deaths which occurred during the trial or within the follow-up period.

h) Particulars concerning a new combination of medicinal substances must be identical to

those required for new medicinal products and must substantiate the safety and efficacy

of the combination.

Total or partial omission of data must be explained. Should unexpected results occur

during the course of the trials, further pre clinical toxicological and pharmacological

tests must be undertaken and reviewed.

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If the medicinal product is intended for long-term administration, particulars shall be

given of any modification of the pharmacological action following repeated

administration, as well as the establishment of long-term dosage.

5.2.1. Reports of bio-pharmaceutics studies

Bio-availability study reports, comparative bio-availability, bio-equivalence study reports,

reports on in vitro and in vivo correlation study, and bio-analytical and analytical methods

shall be provided.

In addition, an assessment of bio-availability shall be undertaken where necessary to

demonstrate bio-equivalence for the medicinal products referred to in Article 10 (1) (a).

5.2.2. Reports of studies pertinent to pharmaco-kinetics using human bio-materials

For the purposes of this Annex, human bio-materials shall mean any proteins, cells, tissues

and related materials derived from human sources that are used in vitro or ex vivo to assess

pharmaco-kinetics properties of drug substances.

In this respect, reports of plasma protein binding study, hepatic metabolism and active

substance interaction studies and studies using other human bio-materials shall be

provided.

5.2.3. Reports of human pharmaco-kinetic studies

a) The following pharmaco-kinetic characteristics shall be described:

— absorption (rate and extent),

— distribution,

— metabolism,

— excretion.

Clinically significant features including the implication of the kinetic data for the

dosage regimen especially for patients at risk, and differences between man and

animal species used in the pre clinical studies, shall be described.

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In addition to standard multiple-sample pharmaco-kinetics studies, population

pharmaco-kinetics analyses based on sparse sampling during clinical studies can also

address questions about the contributions of intrinsic and extrinsic factors to the

variability in the dose- pharmaco-kinetics response relationship. Reports of

pharmaco-kinetic and initial tolerability studies in healthy subjects and in patients,

reports of pharmaco-kinetic studies to assess effects of intrinsic and extrinsic factors,

and reports of population pharmaco-kinetic studies shall be provided.

b) If the medicinal product is normally to be administered concomitantly with other

medicinal products, particulars shall be given of joint administration tests performed

to demonstrate possible modification of the pharmacological action.

Pharmaco-kinetic interactions between the active substance and other medicinal

products or substances shall be investigated.

5.2.4 Reports of human pharmaco-dynamic studies

a) The pharmaco-dynamic action correlated to the efficacy shall be demonstrated

including:

— the dose-response relationship and its time course,

— justification for the dosage and conditions of administration,

— the mode of action, if possible.

The pharmaco-dynamic action not related to efficacy shall be described.

The demonstration of pharmaco-dynamic effects in human beings shall not in itself

be sufficient to justify conclusions regarding any particular potential therapeutic

effect.

b) If the medicinal product is normally to be administered concomitantly with other

medicinal products, particulars shall be given of joint administration tests performed

to demonstrate possible modification of the pharmacological action.

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Pharmaco-dynamic interactions between the active substance and other medicinal

products or substances shall be investigated.

5.2.5. Reports of efficacy and safety studies

5.2.5.1.

S t u d y R e p o r t s o f C o n t r o l l e d C l i n i c a l S t u d i e s P e r t i n e n t t o

t h e C l a i m e d i n d i c a t i o n

In general, clinical trials shall be done as ‘controlled clinical trials’ if possible,

randomised and as appropriate versus placebo and versus an established medicinal

product of proven therapeutic value; any other design shall be justified. The treatment of

the control groups will vary from case to case and also will depend on ethical

considerations and therapeutic area; thus it may, in some instances, be more pertinent to

compare the efficacy of a new medicinal product with that of an established medicinal

product of proven therapeutic value rather than with the effect of a placebo.

(1) As far as possible, and particularly in trials where the effect of the product cannot

be objectively measured, steps shall be taken to avoid bias, including methods of

randomisation and blinding.

(2) The protocol of the trial must include a thorough description of the statistical

methods to be employed, the number and reasons for inclusion of patients

(including calculations of the power of the trial), the level of significance to be

used and a description of the statistical unit. Measures taken to avoid bias,

particularly methods of randomisation, shall be documented. Inclusion of a large

number of subjects in a trial must not be regarded as an adequate substitute for a

properly controlled trial.

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The safety data shall be reviewed taking into account guidelines published by the

Commission, with particular attention to events resulting in changes of dose or need for

concomitant medication, serious adverse events, events resulting in withdrawal, and

deaths. Any patients or patient groups at increased risk shall be identified and particular

attention paid to potentially vulnerable patients who may be present in small numbers,

e.g., children, pregnant women, frail elderly, people with marked abnormalities of

metabolism or excretion etc. The implication of the safety evaluation for the possible

uses of the medicinal product shall be described.

5.2.5.2.

S t u d y r e p o r t s o f u n c o n t r o l l e d c l i n i c a l s t u d i e s r e p o r t

s o f a n a l y s e s o f d a t a f r o m m o r e t h a n o n e s t u d y a n d o t h

e r c l i n i c a l s t u d y r e p o r t s

These reports shall be provided.

5.2.6. Reports of post-marketing experience

If the medicinal product is already authorised in third countries, information shall be given

in respect of adverse reactions of the medicinal product concerned and medicinal products

containing the same active substance(s), in relation to the usage rates if possible.

5.2.7. Case reports forms and individual patient listings

When submitted in accordance with the relevant Guideline published by the Agency, case

report forms and individual patient data listings shall be provided and presented in the

same order as the clinical study reports and indexed by study.

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PART II

SPECIFIC MARKETING AUTHORISATION DOSSIERS AND REQUIREMENTS

Some medicinal products present specific features which are such that all the requirements of the

marketing authorisation application dossier as laid down in Part I of this Annex need to be adapted.

To take account of these particular situations, an appropriate and adapted presentation of the dossier

shall be followed by applicants.

WELL-ESTABLISHED MEDICINAL USE

For medicinal products the active substance(s) of which has/have a ‘well-established

medicinal use’ as referred to Article 10(1)(a)(ii), with recognised efficacy and an acceptable

level of safety, the following specific rules shall apply.

The applicant shall submit Modules 1, 2 and 3 as described in part I of this Annex.

For Modules 4 and 5, a detailed scientific bibliography shall address non-clinical and clinical

characteristics.

The following specific rules shall apply in order to demonstrate the well-established

medicinal use:

a) Factors which have to be taken into account in order to establish a well-established

medicinal use of constituents of medicinal products are:

— the time over which a substance has been used,

— quantitative aspects of the use of the substance,

— the degree of scientific interest in the use of the substance (reflected in the

published scientific literature) and

— the coherence of scientific assessments.

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Therefore different periods of time may be necessary for establishing well-established

use of different substances. In any case, however, the period of time required for

establishing a well established medicinal use of a constituent of a medicinal product

must not be less than one decade from the first systematic and documented use of that

substance as a medicinal product in the Community.

b) The documentation submitted by the applicant should cover all aspects of the safety

and/or efficacy assessment and must include or refer to a review of the relevant

literature, taking into account pre- and post-marketing studies and published scientific

literature concerning experience in the form of epidemiological studies and in particular

of comparative epidemiological studies. All documentation, both favourable and

unfavourable, must be communicated. With respect to the provisions on ‘well-

established medicinal use’ it is in particular necessary to clarify that ‘bibliographic

reference’ to other sources of evidence (post marketing studies, epidemiological studies,

etc.) and not just data related to tests and trials may serve as a valid proof of safety and

efficacy of a product if an application explains and justifies the use of these sources of

information satisfactorily.

c) Particular attention must be paid to any missing information and justification must be

given why demonstration of an acceptable level of safety and/or efficacy can be

supported although some studies are lacking.

d) The non-clinical and/or clinical overviews must explain the relevance of any data

submitted which concern a product different from the product intended for marketing. A

judgement must be made whether the product studied can be considered as similar to the

product, for which application for a marketing authorisation has been made in spite of

the existing differences.

Post-marketing experience with other products containing the same constituents is of

particular importance and applicants should put a special emphasis on this issue.

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ESSENTIALLY SIMILAR MEDICINAL PRODUCTS

a) Applications based upon Article 10(1) (a) (i) (essentially similar products) shall contain

the data described in Modules 1, 2 and 3 of Part I of this Annex provided the applicant

has been granted the consent of the holder of the original marketing authorisation to

cross refer to the content of his Modules 4 and 5.

b) Applications based upon Article 10(1) (a) (iii) (essentially similar products i.e. generics)

shall contain the data described in Modules 1, 2 and 3 of Part I of this Annex together

with data showing bio-availability and bio-equivalence with the original medicinal

product provided the latter is not a biological medicinal product (see Part II, 4 Similar

biological medicinal products).

For these products the non-clinical/clinical overviews/summaries shall particularly focus on

the following elements:

— the grounds for claiming essential similarity;

— a summary of impurities present in batches of the active substance(s) as well as those of

the finished medicinal product (and where relevant decomposition products arising

during storage) as proposed for use in the product to be marketed together with an

evaluation of these impurities;

— an evaluation of the bio-equivalence studies or a justification why studies were not

performed with respect to the guideline on ‘Investigation of Bio-availability and Bio-

equivalence’;

— an update of published literature relevant to the substance and the present application. It

may be acceptable for articles in ‘peer review’ journals to be annotated for this purpose;

— every claim in the summary of product characteristics not known from or inferred from

the properties of the medicinal product and/or its therapeutic group should be discussed

in the non clinical/clinical overviews/summaries and substantiated by published

literature and/or additional studies.

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— if applicable, additional data in order to demonstrate evidence on the equivalence of

safety and efficacy properties of different salts, esters or derivatives of an authorised

active substance should be provided by the applicant when he claims essential

similarity.

ADDITIONAL DATA REQUIRED IN SPECIFIC SITUATIONS

Where the active substance of an essentially similar medicinal product contains the same

therapeutic moiety as the original authorised product associated with a different salt/ester

complex/derivative evidence that there is no change in the pharmaco-kinetics of the moiety,

pharmaco-dynamics and/or in toxicity which could change the safety/efficacy profile shall be

demonstrated. Should this not be the case, this association shall be considered as a new active

substance.

Where a medicinal product is intended for a different therapeutic use or presented in a

different pharmaceutical form or to be administered by different routes or in different doses or

with a different posology, the results of appropriate toxicological and pharmacological tests

and/or of clinical trials shall be provided.

SIMILAR BIOLOGICAL MEDICINAL PRODUCTS

The provisions of Article 10(1)(a) (iii) may not be sufficient in the case of biological

medicinal products. If the information required in the case of essentially similar products

(generics) does not permit the demonstration of the similar nature of two biological medicinal

products, additional data, in particular, the toxicological and clinical profile shall be provided.

When a biological medicinal product as defined in Part I, paragraph 3.2 of this Annex, which

refers to an original medicinal product having been granted a marketing authorisation in the

Community, is submitted for a marketing authorisation by an independent applicant after the

expiry of data protection period, the following approach shall be applied.

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— Information to be supplied shall not be limited to Modules 1, 2 and 3 (pharmaceutical,

chemical and biological data), supplemented with bio-equivalence and bio-availability

data. The type and amount of additional data (i.e. toxicological and other non-clinical

and appropriate clinical data) shall be determined on a case by case basis in accordance

with relevant scientific guidelines.

— Due to the diversity of biological medicinal products, the need for identified studies

foreseen in Modules 4 and 5, shall be required by the competent authority, taking into

account the specific characteristic of each individual medicinal product.

The general principles to be applied are addressed in a guideline taking into account the

characteristics of the concerned biological medicinal product published by the Agency. In

case the originally authorised medicinal product has more than one indication, the efficacy

and safety of the medicinal product claimed to be similar has to be justified or, if necessary,

demonstrated separately for each of the claimed indications.

FIXED COMBINATION MEDICINAL PRODUCTS

Applications based upon Article 10 (1) (b) shall relate to new medicinal products made of at

least two active substances not previously authorised as a fixed combination medicinal

product.

For those applications a full dossier (Modules 1 to 5) shall be provided for the fixed

combination medicinal product. Where applicable, information regarding the manufacturing

sites and the adventitious agents, safety evaluation shall be provided.

DOCUMENTATION FOR APPLICATIONS IN EXCEPTIONAL CIRCUMSTANCES

When, as provided for in Article 22, the applicant can show that he is unable to provide

comprehensive data on the efficacy and safety under normal conditions of use, because:

— the indications for which the product in question is intended are encountered so rarely

that the applicant cannot reasonably be expected to provide comprehensive evidence, or

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— in the present state of scientific knowledge, comprehensive information cannot be

provided, or

— it would be contrary to generally accepted principles of medical ethics to collect such

information,

marketing authorisation may be granted subject to certain specific obligations.

These obligations may include the following:

— the applicant shall complete an identified programme of studies within a time period

specified by the competent authority, the results of which shall form the basis of a

reassessment of the benefit/risk profile,

— the medicinal product in question may be supplied on medical prescription only and

may in certain cases be administered only under strict medical supervision, possibly in a

hospital and in the case of a radio-pharmaceutical, by an authorised person,

— the package leaflet and any medical information shall draw the attention of the medical

practitioner to the fact that the particulars available concerning the medicinal product in

question are as yet inadequate in certain specified respects.

MIXED MARKETING AUTHORISATION APPLICATIONS

Mixed marketing-authorisation applications shall mean marketing-authorisation

application dossiers where Module 4 and/or 5 consists of a combination of reports of

limited non-clinical and/or clinical studies carried out by the applicant and of

bibliographical references. All other Module(s) are in accordance with the structure

described in Part I of this Annex. The competent authority shall accept the proposed

format presented by the applicant on a case by case basis.

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PART III

PARTICULAR MEDICINAL PRODUCTS

This Part lays down specific requirements related to the nature of identified medicinal products.

BIOLOGICAL MEDICINAL PRODUCTS

1.1. Plasma-derived medicinal product

For medicinal products derived from human blood or plasma and by derogation from the

provisions of Module 3, the dossier requirements mentioned in ‘Information related to the

starting and raw materials’, for starting materials made of human blood/plasma may be

replaced by a Plasma Master File certified in accordance with this Part.

a) P r i n c i p l e s

For the purposes of this Annex:

— Plasma Master File shall mean a stand-alone documentation, which is separate

from the dossier for marketing authorisation which provides all relevant detailed

information on the characteristics of the entire human plasma used as a starting

material and/or a raw material for the manufacture of sub/intermediate fractions,

constituents of the excipient and active substance(s), which are part of medicinal

products or medical devices referred to in Directive 2000/70/EC of the European

Parliament and of the Council of 16 November 2000 amending Council Directive

93/42/EC as regards medical devices incorporating stable derivatives of human

blood or human plasma (59).

— Every centre or establishment for fractionation/processing of human plasma shall

prepare and keep updated the set of detailed relevant information referred to in the

Plasma Master File.

OJ L 313, 13.12.2000, p. 22

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— The Plasma Master File shall be submitted to the Agency or to the competent

authority by the applicant for a marketing authorisation or the holder of the

marketing authorisation. Where the applicant for a marketing authorisation or the

marketing authorisation holder differs from the holder of the Plasma Master File,

the Plasma Master File shall be made available to the applicant or marketing

authorisation holder for submission to the competent authority. In any case, the

applicant or marketing authorisation holder shall take responsibility for the

medicinal product.

— The competent authority that is evaluating the marketing authorisation shall await

for the Agency to issue the certificate before deciding on the application.

— Any marketing authorisation dossier containing a human plasma-derived

constituent shall refer to the Plasma Master File corresponding to the plasma used

as a starting/raw material.

C o n t e n t

In accordance with the provisions of Article 109, as amended by Directive 2002/98/EC,

which refers to the requirements for donors and the testing of donations, the Plasma

Master File shall include information on the plasma used as starting/raw material, in

particular:

(1) Plasma origin

(i)

information on centres or establishments in which blood/plasma collection

is carried out, including inspection and approval, and epidemiological data

on blood transmissible infections.

(ii) information on centres or establishments in which testing of donations and

plasma pools is carried out, including inspection and approval status.

(iii) selection/exclusion criteria for blood/plasma donors.

(iv) system in place which enables the path taken by each donation to be traced

from the blood/plasma collection establishment through to finished products

and vice versa.

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(2) Plasma quality and safety

(i) compliance with European Pharmacopoeia Monographs.

(ii) testing of blood/plasma donations and pools for infectious agents, including

information on test methods and, in the case of plasma pools, validation data

on the tests used.

(iii) technical characteristics of bags for blood and plasma collection, including

information on anticoagulants solutions used.

(iv) conditions of storage and transport of plasma.

(v) procedures for any inventory hold and/or quarantine period.

(vi) characterisation of the plasma pool.

(3) System in place between the plasma-derived medicinal product manufacturer

and/or plasma fractionator/processor on the one hand, and blood/plasma collection

and testing centres or establishments on the other hand, which defines the

conditions of their interaction and their agreed specifications.

In addition, the Plasma Master File shall provide a list of the medicinal products

for which the Plasma Master File is valid, whether the medicinal products have

been granted a marketing authorisation or are in the process of being granted such

an authorisation, including medicinal products referred to in Article 2 of Directive

2001/20/EC of the European Parliament and of the Council relating to the

implementation of good clinical practice in the conduct of clinical trials on

medicinal products for human use.

E v a l u a t i o n a n d C e r t i f i c a t i o n

— For medicinal products not yet authorised, the marketing authorisation applicant

shall submit a full dossier to a competent authority, which shall be accompanied

by a separate Plasma Master File where one does not already exist.

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— The Plasma Master File is subject to a scientific and technical evaluation carried

out by the Agency. A positive evaluation shall result in a certificate of compliance

with Community legislation for the Plasma Master File, which shall be

accompanied by the evaluation report. The certificate issued shall apply

throughout the Community.

— The Plasma Master File shall be updated and re-certified on an annual basis.

— Changes subsequently introduced to the terms of a Plasma Master File must

follow evaluation procedure laid down by Commission Regulation (EC) No

542/95 (60) concerning the examination of variations to the terms of a marketing

authorisation falling within the scope of Council regulation (EEC) No 2309/93 of

22 July 1993 laying down Community procedures for the authorisation and

supervision of medicinal products for human and veterinary use and establishing a

European Agency for the Evaluation of Medicinal Products (61). Conditions for

the assessment of these changes are laid down by Regulation (EC) No 1085/2003.

— As a second step to the provisions in the first, second, third and fourth indents, the

competent authority that will grant or has granted the marketing authorisation

shall take into account the certification, re-certification or variation of the Plasma

Master File on the concerned medicinal product(s).

— By derogation from the provisions of the second indent of the present point

(evaluation and certification), where a Plasma Master File corresponds only to

blood/plasma-derived medicinal products the marketing authorisation of which is

restricted to a single Member State, the scientific and technical evaluation of the

said Plasma Master File shall be carried out by the national competent authority of

that Member State.

OJ L 55, 11.3.1995, p. 15

OJ L 214, 24.8.1993, p. 1

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1.2. Vaccines

For vaccines for human use and by derogation from the provisions of Module 3 on ‘Active

substance(s)’, the following requirements when based on the use of a Vaccine Antigen Master

File system shall apply.

The marketing authorisation application dossier of a vaccine other than human influenza

vaccine, shall be required to include a Vaccine Antigen Master File for every vaccine antigen

that is an active substance of this vaccine.

P r i n c i p l e s

For the purposes of this Annex:

— Vaccine Antigen Master File shall mean a stand-alone part of the marketing

authorisation application dossier for a vaccine, which contains all relevant

information of biological, pharmaceutical and chemical nature concerning each of

the active substances, which are part of this medicinal product. The stand-alone

part may be common to one or more monovalent and/or combined vaccines

presented by the same applicant or marketing authorisation holder.

— A vaccine may contain one or several distinct vaccine antigens. There are as many

active substance(s) as vaccine antigen(s) present in a vaccine.

— A combined vaccine contains at least two distinct vaccine antigens aimed at

preventing a single or several infectious diseases.

— A monovalent vaccine is a vaccine, which contains one vaccine antigen aimed at

preventing a single infectious disease.

C o n t e n t

The Vaccine Antigen Master File shall contain the following information extracted from

the relevant part (Active substance) of Module 3 on ‘Quality Data’ as delineated in Part

I of this Annex:

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Active Substance

General Information, including compliance with the relevant monograph(s) of the

European Pharmacopoeia.

Information on the manufacture of the active substance: this heading must cover

the manufacturing process, information on the starting and raw materials, specific

measures on TSEs and adventitious agents safety evaluation and facilities and

equipment.

Characterisation of the active substance

Quality control of the active substance

Reference standard and materials

Container and closure system of the active substance

Stability of the active substance.

E v a l u a t i o n a n d C e r t i f i c a t i o n

— For novel vaccines, which contain a novel vaccine antigen, the applicant shall

submit to a competent authority a full marketing-authorisation application dossier

including all the Vaccine Antigen Master Files corresponding to each single

vaccine antigen that is part of the novel vaccine where no master file already

exists for the single vaccine antigen. A scientific and technical evaluation of each

Vaccine Antigen Master File shall be carried out by the Agency. A positive

evaluation shall result in a certificate of compliance to the European legislation

for each Vaccine Antigen Master File, which shall be accompanied by the

evaluation report. The certificate shall apply throughout the Community.

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— The provisions of the first indent shall also apply to every vaccine, which consists

of a novel combination of vaccine antigens, irrespective of whether or not one or

more of these vaccine antigens are part of vaccines already authorised in the

Community.

— Changes to the content of a Vaccine Antigen Master File for a vaccine authorised

in the Community shall be subject to a scientific and technical evaluation carried

out by the Agency in accordance with the procedure laid down in Commission

Regulation (EC) No 1085/2003. In the case of a positive evaluation the Agency

shall issue a certificate of compliance with Community legislation for the Vaccine

Antigen Master File. The certificate issued shall apply throughout the

Community.

— By derogation from the provisions of the first, second and third indents of the

present point (evaluation and certification), where a Vaccine Antigen Master File

corresponds only to a vaccine which is the subject of a marketing authorisation

which has not been/will not be granted according to a Community procedure, and,

provided the authorised vaccine includes vaccine antigens which have not been

evaluated through a Community procedure, the scientific and technical evaluation

of the said Vaccine Antigen Master File and its subsequent changes, shall be

carried out by the national competent authority that has granted the marketing

authorisation.

— As a second step to the provisions in the first, second, third and fourth indents, the

competent authority that will grant or has granted the marketing authorisation

shall take into account the certification, re-certification or variation of the Vaccine

Antigen Master File on the concerned medicinal product(s).

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RADIO-PHARMACEUTICALS AND PRECURSORS

2.1. Radio-pharmaceuticals

For the purposes of this chapter, applications based upon Articles 6 (2) and 9 shall provide a

full dossier in which the following specific details shall be included:

Module 3

In the context of a radio-pharmaceutical kit, which is to be radio-labelled after supply

by the manufacturer, the active substance is considered to be that part of the formulation

which is intended to carry or bind the radio-nuclide. The description of the

manufacturing method of radio-pharmaceutical kits shall include details of the

manufacture of the kit and details of its recommended final processing to produce the

radioactive medicinal product. The necessary specifications of the radio-nuclide shall be

described in accordance, where relevant, with the general monograph or specific

monographs of the European Pharmacopoeia. In addition, any compounds essential for

the radio-labelling shall be described. The structure of the radio-labelled compound

shall also be described.

For radio-nuclides, the nuclear reactions involved shall be discussed.

In a generator, both mother and daughter radio-nuclides shall be considered as active

substances.

Details of the nature of the radio-nuclide, the identity of the isotope, likely impurities,

the carrier, the use and the specific activity shall be provided.

Starting materials include irradiation target materials.

Considerations on chemical/radiochemical purity and its relationship to bio-distribution

shall be provided.

Radio-nuclide purity, radiochemical purity and specific activity shall be described.

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For generators, details on the testing for mother and daughter radio-nuclides are

required. For generator-eluates, tests for mother radio-nuclides and for other

constituents of the generator system shall be provided.

g) The requirement to express the content of active substances in terms of the mass of

active entities shall only apply to radio-pharmaceutical kits. For radio-nuclides,

radioactivity shall be expressed in Becquerels at a given date and, if necessary, time

with reference to time zone. The type of radiation shall be indicated.

For kits, the specifications of the finished product shall include tests on performance of

products after radio-labelling. Appropriate controls on radiochemical and radio-nuclidic

purity of the radio-labelled compound shall be included. Any material essential for

radio-labelling shall be identified and assayed.

Information on stability shall be given for radio-nuclide generators, radio-nuclide kits

and radio-labelled products. The stability during use of radio-pharmaceuticals in multi-

dose vials shall be documented.

Module 4

It is appreciated that toxicity may be associated with a radiation dose. In diagnosis, this is a

consequence of the use of radio-pharmaceuticals; in therapy, it is the property desired. The

evaluation of safety and efficacy of radio-pharmaceuticals shall, therefore, address

requirements for medicinal products and radiation dosimetry aspects. Organ/tissue exposure

to radiation shall be documented. Absorbed radiation dose estimates shall be calculated

according to a specified, internationally recognised system by a particular route of

administration.

Module 5

The results of clinical trials shall be provided where applicable otherwise justified in the

clinical overviews.

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2.2. Radio-pharmaceutical precursors for radio-labelling purposes

In the specific case of a radio-pharmaceutical precursor intended solely for radio-labelling

purposes, the primary objective shall be to present information which would address the

possible consequences of poor radio-labeling efficiency or in vivo dissociation of the radio-

labeled conjugate, i.e. questions related to the effects produced in the patient by free radio-

nuclide. In addition, it is also necessary to present relevant information relating to

occupational hazards, i.e. radiation exposure to hospital staff and to the environment.

In particular, the following information where applicable shall be provided:

Module 3

The provisions of Module 3 shall apply to the registration of radio-pharmaceutical precursors

as define above (indents a) to i)), where applicable.

Module 4

Concerning single dose and repeat dose toxicity, the results of studies carried out in

conformity with the provisions related to good laboratory practice laid down in Council

Directives 87/18/EEC and 88/320/EEC shall be provided, unless otherwise justified.

Mutagenicity studies on the radio-nuclide are not considered to be useful in this particular

case.

Information relating to the chemical toxicity and disposition of the relevant ‘cold’ nuclide

shall be presented.

Module 5

Clinical information generated from clinical studies using on the precursor itself is not

considered to be relevant in the specific case of a radio-pharmaceutical precursor intended

solely for radio-labelling purposes.

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However, information demonstrating the clinical utility of the radio-pharmaceutical precursor

when attached to relevant carrier molecules shall be presented.

HOMEOPATHIC MEDICINAL PRODUCTS

This section sets out specific provisions on the application of Modules 3 and 4 to homeopathic

medicinal products as defined in Article 1(5).

Module 3

The provisions of Module 3 shall apply to the documents submitted in accordance with

Article 15 in the simplified registration of homeopathic medicinal products referred to in

Article 14(1) as well as to the documents for authorisation of other homeopathic medicinal

products referred to in Article 16(1) with the following modifications.

a) Terminology

The Latin name of the homeopathic stock described in the marketing authorisation

application dossier must be in accordance with the Latin title of the European

Pharmacopoeia or, in absence thereof, by an official pharmacopoeia of a Member State.

Where relevant the traditional name(s) used in each Member State shall be provided.

b) Control of starting materials

The particulars and documents on the starting materials, i.e. all of the materials used

including raw materials and intermediates up to the final dilution to be incorporated into

the finished medicinal product, accompanying the application shall be supplemented by

additional data on the homeopathic stock.

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The general quality requirements shall apply to all of the starting and raw materials as

well as intermediate steps of the manufacturing process up to the final dilution to be

incorporated into the finished medicinal product. If possible, an assay is required if

toxic components are present and if the quality cannot be controlled on final dilution to

be incorporated because of the high dilution degree. Every step of the manufacturing

process from the starting materials up to the final dilution to be incorporated into the

finished medicinal product must be fully described.

In case dilutions are involved, these dilution steps should be done in accordance with

the homeopathic manufacturing methods laid down in the relevant monograph of the

European Pharmacopoeia or, in absence thereof, by an official pharmacopoeia of a

Member State.

Control tests on the finished medicinal product

The general quality requirements shall apply to the homeopathic finished medicinal

products, any exception needs to be duly justified by the applicant.

Identification and assay of all the toxicologically relevant constituents shall be carried

out. If it can be justified that an identification and/or an assay on all the toxicologically

relevant constituents is not possible e.g. due to their dilution in the finished medicinal

product the quality shall be demonstrated by complete validation of the manufacturing

and dilution process.

d) Stability tests

The stability of the finished medicinal product must be demonstrated. Stability data

from the homeopathic stocks are generally transferable to dilutions/triturations obtained

thereof. If no identification or assay of the active substance is possible due to the degree

of dilution, stability data of the pharmaceutical form may be considered.

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The provisions of Module 4 shall apply to the simplified registration of homeopathic

medicinal products referred to in Article 14(1) with the following specifications.

Any missing information must be justified, e.g., justification must be given why

demonstration of an acceptable level of safety can be supported although some studies are

lacking.

HERBAL MEDICINAL PRODUCTS

Applications for herbal medicinal products shall provide a full dossier in which the following

specific details shall be included.

Module 3

The provisions of Module 3, including compliance with monograph(s) of the European

Pharmacopoeia, shall apply to the authorisation of herbal medicinal products. The state of

scientific knowledge at the time when the application is lodged shall be taken into account.

The following aspects specific to herbal medicinal products shall be considered:

(1) H e r b a l s u b s t a n c e s a n d h e r b a l p r e p a r a t i o n s

For the purposes of this Annex the terms ‘herbal substances and preparations’ shall be

considered equivalent to the terms ‘herbal drugs and herbal drug preparations’, as defined in

the European Pharmacopoeia.

With respect to the nomenclature of the herbal substance, the binomial scientific name of

plant (genus, species, variety and author), and chemotype (where applicable), the parts of the

plants, the definition of the herbal substance, the other names (synonyms mentioned in other

Pharmacopoeias) and the laboratory code shall be provided.

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With respect to the nomenclature of the herbal preparation, the binomial scientific name of

plant (genus, species, variety and author), and chemotype (where applicable), the parts of the

plants, the definition of the herbal preparation, the ratio of the herbal substance to the herbal

preparation, the extraction solvent(s), the other names (synonyms mentioned in other

Pharmacopoeias) and the laboratory code shall be provided.

To document the section of the structure for herbal substance(s) and herbal preparation(s)

where applicable, the physical form, the description of the constituents with known

therapeutic activity or markers (molecular formula, relative molecular mass, structural

formula, including relative and absolute stereo-chemistry, the molecular formula, and the

relative molecular mass) as well as other constituent(s) shall be provided.

To document the section on the manufacturer of the herbal substance, the name, address, and

responsibility of each supplier, including contractors, and each proposed site or facility

involved in production/collection and testing of the herbal substance shall be provided, where

appropriate.

To document the section on the manufacturer of the herbal preparation, the name, address,

and responsibility of each manufacturer, including contractors, and each proposed

manufacturing site or facility involved in manufacturing and testing of the herbal preparation

shall be provided, where appropriate.

With respect to the description of manufacturing process and process controls for the herbal

substance, information shall be provided to adequately describe the plant production and plant

collection, including the geographical source of the medicinal plant and cultivation,

harvesting, drying and storage conditions.

With respect to the description of manufacturing process and process controls for the herbal

preparation, information shall be provided to adequately describe the manufacturing process

of the herbal preparation, including description of the processing, solvents and reagents,

purification stages and standardisation.

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With respect to the manufacturing process development, a brief summary describing the

development of the herbal substance(s) and herbal preparation(s) where applicable shall be

provided, taking into consideration the proposed route of administration and usage. Results

comparing the phyto-chemical composition of the herbal substance(s) and herbal

preparation(s) where applicable used in supporting bibliographic data and the herbal

substance(s) and herbal preparation(s), where applicable, contained as active substance(s) in

the herbal medicinal product applied for shall be discussed, where appropriate.

With respect to the elucidation of the structure and other characteristics of the herbal

substance, information on the botanical, macroscopical, microscopical, phyto-chemical

characterisation, and biological activity if necessary, shall be provided.

With respect to the elucidation of the structure and other characteristics of the herbal

preparation, information on the phyto- and physicochemical characterisation, and biological

activity if necessary, shall be provided.

The specifications for the herbal substance(s) and herbal preparation(s) where applicable shall

be provided.

The analytical procedures used for testing the herbal substance(s) and herbal preparation(s)

where applicable shall be provided.

With respect to the validation of analytical procedures, analytical validation information,

including experimental data for the analytical procedures used for testing the herbal

substance(s) and herbal preparation(s) where applicable shall be provided.

With respect to batch analyses, description of batches and results of batch analyses for the

herbal substance(s) and herbal preparation(s) where applicable shall be provided, including

those for pharmacopoeial substances.

Justification for the specifications of the herbal substance(s) and herbal preparation(s) where

applicable shall be provided.

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Information on the reference standards or reference materials used for testing of the herbal

substance(s) and herbal preparation(s) where applicable shall be provided.

Where the herbal substance or the herbal preparation is the subject of a monograph, the

applicant can apply for a certificate of suitability that was granted by the European

Directorate for the Quality of Medicines.

(2) H e r b a l M e d i c i n a l P r o d u c t s

With respect to the formulation development, a brief summary describing the development of

the herbal medicinal product should be provided, taking into consideration the proposed route

of administration and usage. Results comparing the phyto-chemical composition of the

products used in supporting bibliographic data and the herbal medicinal product applied for

shall be discussed, where appropriate.

ORPHAN MEDICINAL PRODUCTS

— In the case of an orphan medicinal product in the meaning of Regulation (EC) No

141/2000, general provisions of Part II-6 (exceptional circumstances) can be applied.

The applicant shall then justify in the non-clinical and clinical summaries the reasons

for which it is not possible to provide the complete information and shall provide a

justification of the benefit/risk balance for the orphan medicinal product concerned.

— When an applicant for an marketing authorisation for an orphan medicinal product

invokes the provisions of Article 10 (1)(a)(ii) and Part II-1 of this Annex (well-

established medicinal use), the systematic and documented use of the concerned

substance can refer — as way of derogation — to the use of that substance in

accordance with the provisions of Article 5 of this Directive.

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PART IV

ADVANCED THERAPY MEDICINAL PRODUCTS

INTRODUCTION

Marketing authorisation applications for advanced therapy medicinal products, as defined in

point (a) of Article 2(1) of Regulation (EC) No 1394/2007, shall follow the format

requirements (Modules 1, 2, 3, 4 and 5) described in Part I of this Annex.

The technical requirements for Modules 3, 4 and 5 for biological medicinal products, as

described in Part I of this Annex, shall apply. The specific requirements for advanced therapy

medicinal products described in sections 3, 4 and 5 of this part explain how the requirements

in Part I apply to advanced therapy medicinal products. In addition, where appropriate and

taking into account the specificities of advanced therapy medicinal products, additional

requirements have been set.

Due to the specific nature of advanced therapy medicinal products, a risk-based approach may

be applied to determine the extent of quality, non-clinical and clinical data to be included in

the marketing authorisation application, in accordance with the scientific guidelines relating

to the quality, safety and efficacy of medicinal products referred to in point 4 of the

‘Introduction and general principles’.

The risk analysis may cover the entire development. Risk factors that may be considered

include: the origin of the cells (autologous, allogeneic, xenogeneic), the ability to proliferate

and/or differentiate and to initiate an immune response, the level of cell manipulation, the

combination of cells with bioactive molecules or structural materials, the nature of the gene

therapy medicinal products, the extent of replication competence of viruses or micro-

organisms used in vivo, the level of integration of nucleic acids sequences or genes into the

genome, the long time functionality, the risk of oncogenicity and the mode of administration

or use.

Relevant available non-clinical and clinical data or experience with other, related advanced

therapy medicinal products may also be considered in the risk analysis.

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Any deviation from the requirements of this Annex shall be scientifically justified in Module

2 of the application dossier. The risk analysis described above, when applied, shall also be

included and described in Module 2. In this case, the methodology followed, the nature of the

identified risks and the implications of the risk based approach for the development and

evaluation program shall be discussed and any deviations from the requirements of this Annex

resulting from the risk analysis shall be described.

DEFINITIONS

For the purposes of this Annex, in addition to the definitions laid down in Regulation (EC) No

1394/2007, the definitions set out in sections 2.1 and 2.2 shall apply.

2.1. Gene therapy medicinal product

Gene therapy medicinal product means a biological medicinal product which has the

following characteristics:

(a) it contains an active substance which contains or consists of a recombinant nucleic acid

used in or administered to human beings with a view to regulating, repairing, replacing,

adding or deleting a genetic sequence;

(b) its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant

nucleic acid sequence it contains, or to the product of genetic expression of this

sequence.

Gene therapy medicinal products shall not include vaccines against infectious diseases.

2.2. Somatic cell therapy medicinal product

Somatic cell therapy medicinal product means a biological medicinal product which has the

following characteristics:

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(a) contains or consists of cells or tissues that have been subject to substantial manipulation

so that biological characteristics, physiological functions or structural properties

relevant for the intended clinical use have been altered, or of cells or tissues that are not

intended to be used for the same essential function(s) in the recipient and the donor;

(b) is presented as having properties for, or is used in or administered to human beings with

a view to treating, preventing or diagnosing a disease through the pharmacological,

immunological or metabolic action of its cells or tissues.

For the purposes of point (a), the manipulations listed in Annex I to Regulation (EC) No

1394/2007, in particular, shall not be considered as substantial manipulations.

SPECIFIC REQUIREMENTS REGARDING MODULE 3

3.1. Specific requirements for all advanced therapy medicinal products

A description of the traceability system that the marketing authorisation holder intends to

establish and maintain to ensure that the individual product and its starting and raw materials,

including all substances coming into contact with the cells or tissues it may contain, can be

traced through the sourcing, manufacturing, packaging, storage, transport and delivery to the

hospital, institution or private practice where the product is used, shall be provided.

The traceability system shall be complementary to, and compatible with, the requirements

established in Directive 2004/23/EC of the European Parliament and of the Council (62), as

regards human cells and tissues other than blood cells, and Directive 2002/98/EC, as regards

human blood cells.

3.2. Specific requirements for gene therapy medicinal products

3.2.1. Introduction: finished product, active substance and starting materials

OJ L 102, 7.4.2004, p. 48

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3.2.1.1.

Gene therapy medicinal product containing recombinant nucleic acid sequence(s) or

genetically modified microorganism(s) or virus(es)

The finished medicinal product shall consist of nucleic acid sequence(s) or genetically

modified microorganism(s) or virus(es) formulated in their final immediate container

for the intended medical use. The finished medicinal product may be combined with a

medical device or active implantable medical device.

The active substance shall consist of nucleic acid sequence(s) or genetically modified

microorganism(s) or virus(es).

3.2.1.2.

Gene therapy medicinal product containing genetically modified cells

The finished medicinal product shall consist of genetically modified cells formulated in

the final immediate container for the intended medical use. The finished medicinal

product may be combined with a medical device or active implantable medical device.

The active substance shall consist of cells genetically modified by one of the products

described in section 3.2.1.1 above.

3.2.1.3.

In the case of products consisting of viruses or viral vectors, the starting materials shall

be the components from which the viral vector is obtained, i.e. the master virus vector

seed or the plasmids used to transfect the packaging cells and the master cell bank of the

packaging cell line.

3.2.1.4.

In the case of products consisting of plasmids, non-viral vectors and genetically

modified microorganism(s) other than viruses or viral vectors, the starting materials

shall be the components used to generate the producing cell, i.e. the plasmid, the host

bacteria and the master cell bank of recombinant microbial cells.

3.2.1.5.

In the case of genetically modified cells, the starting materials shall be the components

used to obtain the genetically modified cells, i.e. the starting materials to produce the

vector, the vector and the human or animal cells. The principles of good manufacturing

practice shall apply from the bank system used to produce the vector onwards.

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3.2.2. Specific requirements

In addition to the requirements set out in sections 3.2.1 and 3.2.2 of Part I of this Annex,

the following requirements shall apply:

(a) information shall be provided on all the starting materials used for the manufacture

of the active substance, including the products necessary for the genetic modification

of human or animal cells and, as applicable, subsequent culture and preservation of

the genetically modified cells, taking into consideration the possible absence of

purification steps;

(b) for products containing a microorganism or a virus, data on the genetic modification,

sequence analysis, attenuation of virulence, tropism for specific tissues and cell

types, cell cycle dependence of the microorganism or virus, pathogenicity and

characteristics of the parental strain shall be provided;

relevant sections of the dossier, and in particular replication competent virus

contaminants if the vector is designed to be replication incompetent;

(d) for plasmids, quantification of the different plasmid forms shall be undertaken

throughout the shelf life of the product;

(e) for genetically modified cells, the characteristics of the cells before and after the

genetic modification, as well as before and after any subsequent freezing/storage

procedures, shall be tested.

For genetically modified cells, in addition to the specific requirements for gene therapy

medicinal products, the quality requirements for somatic cell therapy medicinal products

and tissue engineered products (see section 3.3) shall apply.

3.3. Specific requirements for somatic cell therapy medicinal products and tissue engineered

products

3.3.1. Introduction: finished product, active substance and starting materials

The finished medicinal product shall consist of the active substance formulated in its

immediate container for the intended medical use, and in its final combination for

combined advanced therapy medicinal products.

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The active substance shall be composed of the engineered cells and/or tissues.

Additional substances (e.g. scaffolds, matrices, devices, biomaterials, biomolecules and/or

other components) which are combined with manipulated cells of which they form an

integral part shall be considered as starting materials, even if not of biological origin.

Materials used during the manufacture of the active substance (e.g. culture media, growth

factors) and that are not intended to form part of the active substance shall be considered as

raw materials.

3.3.2. Specific requirements

In addition to the requirements set out in sections 3.2.1 and 3.2.2 of Part I of this Annex,

the following requirements shall apply:

3.3.2.1.

Starting materials

(a) Summary information shall be provided on donation, procurement and testing of

the human tissue and cells used as starting materials and made in accordance with

Directive 2004/23/EC. If non-healthy cells or tissues (e.g. cancer tissue) are used

as starting materials, their use shall be justified.

(b) If allogeneic cell populations are being pooled, the pooling strategies and

measures to ensure traceability shall be described.

shall be addressed as part of the validation of the manufacturing process,

characterisation of the active substance and the finished product, development of

assays, setting of specifications and stability.

(d) For xenogeneic cell-based products, information on the source of animals (such

as geographical origin, animal husbandry, age), specific acceptance criteria,

measures to prevent and monitor infections in the source/donor animals, testing of

the animals for infectious agents, including vertically transmitted micro-organisms

and viruses, and evidence of the suitability of the animal facilities shall be

provided.

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(e) For cell-based products derived from genetically modified animals, the specific

characteristics of the cells related to the genetic modification shall be described. A

detailed description of the method of creation and the characterisation of the

transgenic animal shall be provided.

(f) For the genetic modification of the cells, the technical requirements specified in

section 3.2 shall apply.

(g) The testing regimen of any additional substance (scaffolds, matrices, devices,

biomaterials, biomolecules or other components), which are combined with

engineered cells of which they form an integral part, shall be described and

justified.

(h) For scaffolds, matrices and devices that fall under the definition of a medical

device or active implantable medical device, the information required under

section 3.4 for the evaluation of the combined advanced therapy medicinal

product shall be provided.

3.3.2.2.

Manufacturing process

(a) The manufacturing process shall be validated to ensure batch and process

consistency, functional integrity of the cells throughout manufacturing and

transport up to the moment of application or administration, and proper

differentiation state.

(b) If cells are grown directly inside or on a matrix, scaffold or device, information

shall be provided on the validation of the cell culture process with respect to cell-

growth, function and integrity of the combination.

3.3.2.3.

Characterisation and control strategy

(a) Relevant information shall be provided on the characterisation of the cell

population or cell mixture in terms of identity, purity (e.g. adventitious microbial

agents and cellular contaminants), viability, potency, karyology, tumourigenicity

and suitability for the intended medicinal use. The genetic stability of the cells

shall be demonstrated.

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(b) Qualitative and, where possible, quantitative information on product- and process-

related impurities, as well as on any material capable of introducing degradation

products during production, shall be provided. The extent of the determination of

impurities shall be justified.

product, but only on key intermediates and/or as in-process testing, this shall be

justified.

(d) Where biologically active molecules (such as growth factors, cytokines) are

present as components of the cell-based product, their impact and interaction with

other components of the active substance shall be characterised.

(e) Where a three-dimensional structure is part of the intended function, the

differentiation state, structural and functional organisation of the cells and, where

applicable, the extracellular matrix generated shall be part of the characterisation

for these cell-based products. Where needed, non-clinical investigations shall

complement the physicochemical characterisation.

3.3.2.4. Excipients

For excipient(s) used in cell or tissue-based medicinal products (e.g. the components of

the transport medium), the requirements for novel excipients, as laid down in Part I of

this Annex, shall apply, unless data exists on the interactions between the cells or tissues

and the excipients.

3.3.2.5.

Developmental studies

The description of the development program shall address the choice of materials and

processes. In particular, the integrity of the cell population as in the final formulation

shall be discussed.

3.3.2.6.

Reference materials

A reference standard, relevant and specific for the active substance and/or the finished

product, shall be documented and characterised.

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3.4. Specific requirements for advanced therapy medicinal products containing devices

3.4.1. Advanced therapy medicinal product containing devices as referred to in Article 7 of

Regulation (EC) No 1394/2007

A description of the physical characteristics and performance of the product and a

description of the product design methods shall be provided.

The interaction and compatibility between genes, cells and/or tissues and the structural

components shall be described.

3.4.2. Combined advanced therapy medicinal products as defined in Article 2(1)(d) of Regulation

(EC) No 1394/2007

For the cellular or tissue part of the combined advanced therapy medicinal product, the

specific requirements for somatic cell therapy medicinal products and tissue engineered

products set out in section 3.3 shall apply and, in the case of genetically modified cells, the

specific requirements for gene therapy medicinal products set out in section 3.2 shall

apply.

The medical device or the active implantable medical device may be an integral part of the

active substance. Where the medical device or active implantable medical device is

combined with the cells at the time of the manufacture or application or administration of

the finished products, they shall be considered as an integral part of the finished product.

Information related to the medical device or the active implantable medical device (which is

an integral part of the active substance or of the finished product) which is relevant for the

evaluation of the combined advanced therapy medicinal product shall be provided. This

information shall include:

(a) information on the choice and intended function of the medical device or implantable

medical device and demonstration of compatibility of the device with other

components of the product;

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(b) evidence of conformity of the medical device part with the essential requirements

laid down in Annex I to Council Directive 93/42/EEC (63), or of conformity of the

active implantable device part with the essential requirements laid down in Annex 1

to Council Directive 90/385/EEC (64);

medical device with the BSE/TSE requirements laid down in Commission Directive

2003/32/EC (65);

(d) where available, the results of any assessment of the medical device part or the active

implantable medical device part by a notified body in accordance with Directive

93/42/EEC or Directive 90/385/EEC.

The notified body which has carried out the assessment referred to in point (d) of this

section shall make available on request of the competent authority assessing the

application, any information related to the results of the assessment in accordance with

Directive 93/42/EEC or Directive 90/385/EEC. This may include information and

documents contained in the conformity assessment application concerned, where necessary

for the evaluation of the combined advanced therapy medicinal product as a whole.

SPECIFIC REQUIREMENTS REGARDING MODULE 4

4.1. Specific requirements for all advanced therapy medicinal products

The requirements of Part I, Module 4 of this Annex on the pharmacological and toxicological

testing of medicinal products may not always be appropriate due to unique and diverse

structural and biological properties of advanced therapy medicinal products. The technical

requirements in sections 4.1, 4.2 and 4.3 below explain how the requirements in Part I of this

Annex apply to advanced therapy medicinal products. Where appropriate and taking into

account the specificities of advanced therapy medicinal products, additional requirements

have been set.

OJ L 169, 12.7.1993, p. 1

OJ L 189, 20.7.1990, p. 17

OJ L 105, 26.4.2003, p. 18

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The rationale for the non-clinical development and the criteria used to choose the relevant

species and models (in vitro and in vivo) shall be discussed and justified in the non-clinical

overview. The chosen animal model(s) may include immuno-compromised, knockout,

humanised or transgenic animals. The use of homologous models (e.g. mouse cells analysed

in mice) or disease mimicking models shall be considered, especially for immunogenicity and

immunotoxicity studies.

In addition to the requirements of Part I, the safety, suitability and biocompatibility of all

structural components (such as matrices, scaffolds and devices) and any additional substances

(such as cellular products, biomolecules, biomaterials, and chemical substances), which are

present in the finished product, shall be provided. Their physical, mechanical, chemical and

biological properties shall be taken into account.

4.2. Specific requirements for gene therapy medicinal products

In order to determine the extent and type of non-clinical studies necessary to determine the

appropriate level of non-clinical safety data, the design and type of the gene therapy medicinal

product shall be taken into account.

4.2.1. Pharmacology

(a) In vitro and in vivo studies of actions relating to the proposed therapeutic use (i.e.

pharmacodynamic ‘proof of concept’ studies) shall be provided using models and

relevant animal species designed to show that the nucleic acid sequence reaches its

intended target (target organ or cells) and provides its intended function (level of

expression and functional activity). The duration of the nucleic acid sequence

function and the proposed dosing regimen in the clinical studies shall be provided.

(b) Target selectivity: When the gene therapy medicinal product is intended to have a

selective or target-restricted functionality, studies to confirm the specificity and

duration of functionality and activity in target cells and tissues shall be provided.

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4.2.2. Pharmacokinetics

(a) Biodistribution studies shall include investigations on persistence, clearance and

mobilisation. Biodistribution studies shall additionally address the risk of germline

transmission.

(b) Investigations of shedding and risk of transmission to third parties shall be provided

with the environmental risk assessment, unless otherwise duly justified in the

application on the basis of the type of product concerned.

4.2.3. Toxicology

(a) Toxicity of the finished gene therapy medicinal product shall be assessed. In

addition, depending on the type of product, individual testing of active substance and

excipients shall be taken into consideration, the in vivo effect of expressed nucleic

acid sequence-related products which are not intended for the physiological function

shall be evaluated.

(b) Single-dose toxicity studies may be combined with safety pharmacology and

pharmacokinetic studies, e.g. to investigate persistence.

subjects is intended. The mode and scheme of administration shall closely reflect the

planned clinical dosing. For those cases where single dosing may result in prolonged

functionality of the nucleic acid sequence in humans, repeated toxicity studies shall

be considered. The duration of the studies may be longer than in standard toxicity

studies depending on the persistence of the gene therapy medicinal product and the

anticipated potential risks. A justification for the duration shall be provided.

(d) Genotoxicity shall be studied. However, standard genotoxicity studies shall only be

conducted when they are necessary for testing a specific impurity or a component of

the delivery system.

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(e) Carcinogenicity shall be studied. Standard lifetime rodent carcinogenicity studies

shall not be required. However, depending on the type of product, the tumourigenic

potential shall be evaluated in relevant in vivo/in vitro models.

(f) Reproductive and developmental toxicity: Studies on the effects on fertility and

general reproductive function shall be provided. Embryo-foetal and perinatal toxicity

studies and germline transmission studies shall be provided, unless otherwise duly

justified in the application on the basis of the type of product concerned.

(g) Additional toxicity studies

— Integration studies: integration studies shall be provided for any gene therapy

medicinal product, unless the lack of these studies is scientifically justified, e.g.

because nucleic acid sequences will not enter into the cell nucleus. For gene

therapy medicinal products not expected to be capable of integration, integration

studies shall be performed, if biodistribution data indicate a risk for germline

transmission.

— Immunogenicity and immunotoxicity: potential immunogenic and immunotoxic

effects shall be studied.

4.3. Specific requirements for somatic cell therapy medicinal products and tissue engineered

products

4.3.1. Pharmacology

(a) The primary pharmacological studies shall be adequate to demonstrate the proof of

concept. The interaction of the cell-based products with the surrounding tissue shall

be studied.

(b) The amount of product needed to achieve the desired effect/the effective dose, and,

depending on the type of product, the frequency of dosing shall be determined.

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physiological effects that are not related to the desired therapeutic effect of the

somatic cell therapy medicinal product, of the tissue engineered product or of

additional substances, as biologically active molecules besides the protein(s) of

interest might be secreted or the protein(s) of interest could have unwanted target

sites.

4.3.2. Pharmacokinetics

(a) Conventional pharmacokinetic studies to investigate absorption, distribution,

metabolism and excretion shall not be required. However, parameters such as

viability, longevity, distribution, growth, differentiation and migration shall be

investigated, unless otherwise duly justified in the application on the basis of the type

of product concerned.

(b) For somatic cell therapy medicinal products and tissue engineered products,

producing systemically active biomolecules, the distribution, duration and amount of

expression of these molecules shall be studied.

4.3.3. Toxicology

(a) The toxicity of the finished product shall be assessed. Individual testing of active

substance(s), excipients, additional substances and any process-related impurities

shall be taken into consideration.

(b) The duration of observations may be longer than in standard toxicity studies and the

anticipated lifespan of the medicinal product, together with its pharmacodynamic and

pharmacokinetic profile, shall be taken into consideration. A justification of the

duration shall be provided.

with regard to the tumourigenic potential of the product.

(d) Potential immunogenic and immunotoxic effects shall be studied.

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(e) In the case of cell-based products containing animal cells, the associated specific

safety concerns such as transmission to humans of xenogeneic pathogens shall be

addressed.

SPECIFIC REQUIREMENTS REGARDING MODULE 5

5.1. Specific requirements for all advanced therapy medicinal products

5.1.1. The specific requirements in this section of Part IV are additional requirements to those set

in Module 5 in Part I of this Annex.

5.1.2. Where the clinical application of advanced therapy medicinal products requires specific

concomitant therapy and involve surgical procedures, the therapeutic procedure as a whole

shall be investigated and described. Information on the standardisation and optimisation of

those procedures during clinical development shall be provided.

Where medical devices used during the surgical procedures for application, implantation or

administration of the advanced therapy medicinal product may have an impact on the

efficacy or safety of the advanced therapy product, information on these devices shall be

provided.

Specific expertise required to carry out the application, implantation, administration or

follow-up activities shall be defined. Where necessary, the training plan of health care

professionals on the use, application, implantation or administration procedures of these

products shall be provided.

5.1.3. Given that, due to the nature of advanced therapy medicinal products, their manufacturing

process may change during clinical development, additional studies to demonstrate

comparability may be required.

5.1.4. During clinical development, risks arising from potential infectious agents or the use of

material derived from animal sources and measures taken to reduce such risk shall be

addressed.

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5.1.5. Dose selection and schedule of use shall be defined by dose-finding studies.

5.1.6. The efficacy of the proposed indications shall be supported by relevant results from

clinical studies using clinically meaningful endpoints for the intended use. In certain

clinical conditions, evidence of long-term efficacy may be required. The strategy to

evaluate long-term efficacy shall be provided.

5.1.7. A strategy for the long-term follow-up of safety and efficacy shall be included in the risk

management plan.

5.1.8. For combined advanced therapy medicinal products, the safety and efficacy studies shall

be designed for and performed on the combined product as a whole.

5.2. Specific requirements for gene therapy medicinal products

5.2.1. Human pharmacokinetic studies

Human pharmacokinetic studies shall include the following aspects:

(a) shedding studies to address the excretion of the gene therapy medicinal products;

(b) biodistribution studies;

(e.g. expressed proteins or genomic signatures).

5.2.2. Human pharmacodynamic studies

Human pharmacodynamic studies shall address the expression and function of the nucleic

acid sequence following administration of the gene therapy medicinal product.

5.2.3. Safety studies

Safety studies shall address the following aspects:

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(a) emergence of replication competent vector;

(b) emergence of new strains;

(d) neoplastic proliferation due to insertional mutagenicity.

5.3. Specific requirements for somatic cell therapy medicinal products

5.3.1. Somatic cell therapy medicinal products where the mode of action is based on the

production of defined active biomolecule(s)

For somatic cell therapy medicinal products where the mode of action is based on the

production of defined active biomolecule(s), the pharmacokinetic profile (in particular

distribution, duration and amount of expression) of those molecules shall be addressed, if

feasible.

5.3.2 Biodistribution, persistence and long-term engraftment of the somatic cell therapy

medicinal product components

The biodistribution, persistence and long-term engraftment of the somatic cell therapy

medicinal product components shall be addressed during the clinical development.

5.3.3. Safety studies

Safety studies shall address the following aspects:

(a) distribution and engrafting following administration;

(b) e ctopic engraftment;

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5.4. Specific requirements for tissue engineered products

5.4.1 Pharmacokinetic studies

Where conventional pharmacokinetic studies are not relevant for tissue engineered

products, the biodistribution, persistence and degradation of the tissue engineered product

components shall be addressed during the clinical development.

5.4.2. Pharmacodynamic studies

Pharmacodynamic studies shall be designed and tailored to the specificities of tissue

engineered products. The evidence for the ‘proof of concept’ and the kinetics of the

product to obtain the intended regeneration, repairing or replacement shall be provided.

Suitable pharmacodynamic markers, related to the intended function(s) and structure shall

be taken into account.

5.4.3 Safety studies

Section 5.3.3 shall apply.

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ANNEX III

CONDITIONS FOR QUALIFICATION OF A QUALIFIED PERSON

The qualified person shall be in possession of evidence of formal qualifications awarded

on completion of a university course of study, or a course recognised as equivalent by

the Member State concerned, extending over a period of at least four years of theoretical

and practical study, hold a university degree in one or more of the following scientific

disciplines: pharmacy, medicine, veterinary medicine, chemistry, pharmaceutical chemistry

and technology, biology, biomedical engineering and biotechnology, chemical

engineering.

However, the minimum duration of the university course may be three and a half years

where the course is followed by a period of theoretical and practical training of a

minimum duration of one year and including a training period of at least six months in a

pharmacy open to the public, corroborated by an examination at university level.

Where two university courses or two courses recognised by the Member State as

equivalent co-exist in a Member State and where one of these extends over four years

and the other over three years, the three-year course leading to evidence of formal

qualifications awarded on completion of a university course or its recognised equivalent

shall be considered to fulfil the condition of duration referred to in the second

subparagraph in so far as evidence of formal qualifications awarded on completion of

both courses are recognised as equivalent by the Member State in question.

The course shall include theoretical and practical study bearing upon at least the

following basic subjects:

(a) Physics

(b) General and inorganic Chemistry

(c) Organic chemistry

(d) Analytical chemistry

(e) Pharmaceutical chemistry, including analysis of medicinal products

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(f)

Biochemistry

(g) Physiology

(h) Microbiology

(i)

Pharmacology

(j)

Pharmaceutical technology

(k) Toxicology.

Studies in these subjects shall be so balanced as to enable the person concerned to fulfil

the obligations specified in Article 153.

In so far as evidence of formal qualifications mentioned in the first subparagraph do not

fulfil the criteria laid down in this paragraph, the competent authority of the Member

State shall ensure that the person concerned provides evidence of adequate knowledge of

the subjects involved.

The qualified person shall have acquired practical full-time experience over at least two years

or equivalent experience acquired over proportionally longer period of time, in one or

more undertakings or entities not engaged in an economic activity that are authorised

manufacturers, obtaining sufficient knowledge of manufacture, testing, supply chains, good

manufacturing practice and pharmaceutical quality systems as well as regulatory processes

and dossier content for ensuring the quality of medicinal products. The duration of practical

experience may be reduced by one year by the competent authority of the Member State

where a university course lasts for at least five years.

A qualified person shall be in possession of a diploma, certificate or other evidence of formal

qualifications awarded on completion of a university course of study, or a course recognised

as equivalent by the Member State concerned, extending over a period of at least four years of

theoretical and practical study in one of the following scientific disciplines: pharmacy,

medicine, veterinary medicine, chemistry, pharmaceutical chemistry and technology, biology.

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However, the minimum duration of the university course may be three and a half years where

the course is followed by a period of theoretical and practical training of a minimum duration

of one year and including a training period of at least six months in a pharmacy open to the

public, corroborated by an examination at university level.

Where two university courses or two courses recognised by the State as equivalent co-exist in

a Member State and where one of these extends over four years and the other over three years,

the three-year course leading to a diploma, certificate or other evidence of formal

qualifications awarded on completion of a university course or its recognised equivalent shall

be considered to fulfil the condition of duration referred to in the second subparagraph in so

far as the diplomas, certificates or other evidence of formal qualifications awarded on

completion of both courses are recognised as equivalent by the Member State in question.

The course shall include theoretical and practical study bearing upon at least the following

basic subjects:

(a) Experimental physics

(b) General and inorganic chemistry

(d) Analytical chemistry

(e) Pharmaceutical chemistry, including analysis of medicinal products

(f)

General and applied biochemistry (medical)

(g) Physiology

(h) Micro biology

(i)

Pharmacology

(j)

Pharmaceutical technology

(k) Toxicology

(l)

Pharmacognosy (study of the composition and effects of the natural active

substances of plant and animal origin).

Studies in these subjects should be so balanced as to enable the person concerned to fulfil the

obligations specified in Article 153.

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In so far as certain diplomas, certificates or other evidence of formal qualifications mentioned

in the first subparagraph do not fulfil the criteria laid down in this paragraph, the competent

authority of the Member State shall ensure that the person concerned provides evidence of

adequate knowledge of the subjects involved.

The qualified person shall have acquired practical experience over at least two years, in one or

more undertakings or not-for-profit entities that are authorised to manufacture medicinal

products, in the activities of qualitative analysis of medicinal products, of quantitative

analysis of active substances and of the testing and checking necessary to ensure the quality of

medicinal products.

A person engaging in the activities of the person referred to in Article 152 from the time of

the application of Second Council Directive 75/319/EEC66, in a Member State without

complying with the provisions of this Annex shall be eligible to continue to engage in those

activities within the Union.

The holder of a diploma, certificate or other evidence of formal qualifications awarded on

completion of a university course — or a course recognised as equivalent by the Member

State concerned — in a scientific discipline allowing them to engage in the activities of the

person referred to in Article 48 in accordance with the laws of that Member State may — if

they began their course prior to 21 May 1975 — be considered as qualified to carry out in that

Member State the duties of the person referred to in Article 152 provided that they have

previously engaged in the following activities for at least two years before 21 May 1985

following notification of this directive in one or more undertakings or not-for-profit entities

not engaged in an economic activity authorised to manufacture: production supervision or

qualitative and quantitative analysis of active substances, and the necessary testing and

checking under the direct authority of the person referred to in Article 152 to ensure the

quality of the medicinal products.

Second Council Directive 75/319/EEC of 20 May 1975 on the approximation of provisions laid down
by Law, Regulation or Administrative Action relating to proprietary medicinal products (OJ L 147,
9.6.1975, p. 13). Directive is not in force anymore.

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ANNEX IV

LABELLING PARTICULARS

The following particulars shall appear on the outer packaging of medicinal products or, where there

is no outer packaging, on the immediate packaging:

(a) the name of the medicinal product, (including in Braille), followed by its strength, if

appropriate (including in Braille), and pharmaceutical form (including in Braille, if

appropriate), and, if appropriate, whether it is intended for babies, children or adults; where

the medicinal product contains up to three active substances, the international non-proprietary

name (INN) shall be included, or, if one does not exist, the common name;

(b) a statement of the active substances expressed qualitatively and quantitatively per doseage or

unit or according to the form of administration for a given volume or weight, using their

common names;

medicinal product;

(d) a list of those excipients, expressed qualitatively, known to have a recognised action or

effect and included in the detailed guidance published pursuant to Article 68; in the case of

injectable medicinal products, topical preparations or eye drops, all excipients shall be

listed;

(e) the method of administration and, if necessary, the route(s) of administration. Space shall be

provided for the prescribed dose to be indicated;

(f)

if appropriate, a special warning that the medicinal product must be stored out of the reach

and sight of children;

(g) a special warning, if this is necessary for the medicinal product;

(h) the expiry date in clear terms (month/year);

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(i)

special storage precautions, if any;

(j)

specific precautions relating to the disposal of unused medicinal products or waste derived

from medicinal products, where appropriate, as well as reference to any appropriate collection

system in place;

(k) the name and address of the marketing authorisation holder and, where applicable, the name

of the representative appointed by the holder to represent them;

(l)

the number of the marketing authorisation for placing the medicinal product on the market;

(m) the manufacturer's batch number;

(n) in the case of non-prescription medicinal products, instructions for use;

(o) for medicinal products other than radiopharmaceuticals referred to in Article 67(1), safety

features enabling wholesale distributors and persons authorised or entitled to supply medicinal

products to the public to:

(i)

verify the authenticity of the medicinal product, and

(ii) identify individual packs,



as well as a device allowing verification of whether the outer packaging has been

tampered with.

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ANNEX V

CONTENTS OF SUMMMARY PRODUCT CHARACTERISTICS

The summary of product characteristics shall contain, in the order indicated below, the following

information:

(1) name of the medicinal product followed by the strength, if appropriate, and the

pharmaceutical form.

(2) qualitative and quantitative composition in terms of the active substances and of the

excipients, knowledge of which is essential for proper administration of the medicinal

product. The usual common name or chemical description shall be used.

(3) pharmaceutical form.

(4) clinical particulars:

(a) therapeutic indications,

(b) posology and method of administration for adults and, where necessary for children,

special warnings and precautions for use and, in the case of immunological medicinal (d)

products, any special precautions to be taken by persons handling such medicinal

products and administering them to patients, together with any precautions to be taken

by the patient,

(e) interaction with other medicinal products and other forms of interactions,

use during pregnancy, and lactation breastfeeding, and information on influence on

fertility,

(f)

effects on ability to drive and to use machines,

(g) undesirable effects including standardised text expressly asking healthcare

professionals to report any suspected adverse reaction in accordance with the

national reporting system referred to in Article 106(1) and specifying the different

ways of reporting available (electronic reporting, postal address or others) in

compliance with Article 106(1), second subparagraph;

(h) overdose (symptoms, emergency procedures, antidotes).

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(5) pharmacological properties:

(a) pharmacodynamic properties,

(b) pharmacokinetic properties,

(6) pharmaceutical particulars:

(a) list of excipients,

(b) major incompatibilities,

medicinal product or when the immediate packaging is opened for the first time,

(d) special precautions for storage,

(e) nature and contents of container,

(f) special precautions for disposal of a used medicinal product or waste materials derived

from such medicinal product, if appropriate. In case of antimicrobial medicinal products

in addition to the precautions a warning that inappropriate disposal of the medicinal

product contributes to antimicrobial resistance.

(7) marketing authorisation holder.

(8) marketing authorisation numbers.

(9) date of the first marketing authorisation or renewal of the marketing authorisation.

(10) date of revision of the text.

(11) for radiopharmaceuticals, full details of internal radiation dosimetry.

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(12) for radiopharmaceuticals, additional detailed instructions for extemporaneous preparation and

quality control of such preparation and, where appropriate, maximum storage time during

which any intermediate preparation such as an eluate or the ready-to-use pharmaceutical will

conform with its specifications.

For marketing authorisations under Articles 9 to 12 and subsequent variations, those parts of the

summary of product characteristics of the reference medicinal product referring to indications or

dosage forms that are still covered by patent law at the time when a generic or biosimilar medicinal

product is placed on the market need not be included.

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ANNEX VI

CONTENTS OF PACKAGE LEAFLET

The package leaflet shall contain, in the order indicated below, the following information:

(1) for the identification of the medicinal product:

(a) the name of the medicinal product followed by its strength, if appropriate, and

pharmaceutical form, and, if appropriate, whether it is intended for babies, children or

adults. The common name shall be included where the medicinal product contains only

one active substance and if its name is an invented name Where the medicinal product

contains up to three active substances, the international non-proprietary name

(INN) shall be included, or, if one does not exist, the common name;

(b) the pharmaco-therapeutic group or type of activity in terms easily comprehensible for

the patient;

(2)

the therapeutic indications;

(3)

a list of information that is necessary before the medicinal product is taken:

(a) contra-indications;

(b) appropriate precautions for use;

alcohol, tobacco, food and herbal products) that may affect the action of the medicinal

product;

(d) special warnings;

(4)

the necessary and usual instructions for proper use, and in particular:

(a) the doseage/posology,

(b) the method and, if necessary, route of administration;

the medicinal product may or must be administered;



and, as appropriate, depending on the nature of the medicinal product:

(d) the duration of treatment, where it should be limited;

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(e) the action to be taken in case of an overdose (such as symptoms, emergency

procedures), if applicable;

(f)

what to do when one or more doses have not been taken;

(g) indication, if necessary, of the risk of withdrawal effects;

(h) a specific recommendation to consult the doctor or the pharmacist, as appropriate, for

any clarification on the use of the medicinal product;

(5) a description of the adverse reactions that may occur under normal use of the medicinal

product and, if necessary, the action to be taken in such a case – including standardised text

expressly asking patients to communicate any suspected adverse reaction to their doctor,

pharmacist, healthcare professional or directly to the national reporting system referred

to in Article 106(1), and specifying the different ways of reporting available (electronic

reporting, postal address or others) in compliance with Article 106(1), second

subparagraph;

(6)

references to the following:

(a) the expiry date indicated on the label, with a warning against using the medicinal

product after that date;

(b) where appropriate, special storage precautions;

(d) the full qualitative composition (in active substances and excipients) and the

quantitative composition in active substances, using common names, for each

presentation of the medicinal product;

(e) for each presentation of the medicinal product, the pharmaceutical form and content in

weight, volume or units of dosage;

(f)

information on where the leaflet is available in formats accessible for persons with

disabilities;

(g) the name, and address and e-mail address of the marketing authorisation holder and,

where applicable, the name of their appointed representatives in the Member States;

(h) the name and address of the manufacturer.

(7)

the date on which the package leaflet was last revised;

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(8) for antimicrobials, a section that contains the global antimicrobial resistance symbol,

specific information about the medicinal product concerned and information on

antimicrobial resistance and the importance of appropriate use and disposal of

antimicrobials referred to in Article 69 paragraph 2 warning that improper use and

disposal of the medicinal product contributes to antimicrobial resistance.

The list set out in point (3) shall:

(a) take into account the particular condition of certain categories of users (children, pregnant or

breastfeeding women, older adults elderly, persons with specific pathological conditions and

persons with disabilities);

(b) mention, if appropriate, possible effects on the ability to drive vehicles or to operate

machinery;

medicinal product and that are included in the detailed guidance referred to in Article 77.

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ANNEX VII

AREAS FOR ADAPTED FRAMEWORKS REFERRED TO IN ARTICLE 28

Phage-containing medicinal products, in cases where the medicinal product has a variable

composition depending on the specific clinical context.

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ANNEX VIII

CORRELATION TABLE

Directive 2001/83 (EC)

Regulation (EC) No 1901/2006

This Directive

Art. 2(1)

Art. 1(1) and (2)

Art. 2(2)

Art. 1(4)

Art. 2(3)

Art. 1(3) and 142(1), second

sentence

Art. 3 (1), (2) and (3)

Art. 1(5), point (a), (b) and (c)

Art. 3 (7)

Art. 2 (1) and (2)

Art 4(4)

Art. 1(10), point (a)

Art. 110

Art. 1(7)

Art. 4(3)

Art. 1(9)

Art. 4(5)

Art.1(8)

Art. 5(1)

Art. 3(1)

Art. 5(2)

Art. 3(2)

Art. 5(3)

Art. 3(3)

Art. 5(4)

Art. 3(4)

Art. 6(1)

Art. 5

Art. 6(2)

Art. 16(1)

Art. 7

Art. 16(2)

Art. 6(1)

Art. 5(1)

Art. 8(3)

Art. 6(2) and Annex I

Art. 8(3), 2nd and 3rd

subparagraphs

Art. 6(3) and (4)

Art. 7 and Art. 8

Art. 6(5)

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Art. 9

Art. 6 (6)

Art. 12

Art. 7

Art. 10(1), 1st subparagraph

Art. 9(1)

Art. 10(2), point (b), 3th sentence

Art. 9(3), second subparagraph

Art. 10(1), 3rd subparagraph

Art. 9(3)

Art. 10(2), point (b), 2nd sentence

Art. 9(4)

Art. 10(3)

Art. 10

Art. 10(4)

Art. 11

Art. 10a

Art. 13

Art. 10c

Art. 14

Art. 17(1), 1st subparagraph

Art. 30

Art. 17(1), 2nd subparagraph

Art. 33(1) and (2), Art. 35

Art. 17(2)

Art. 33(3)

Art. 18

Art. 33(4)

Art. 19(1)

Art. 29(1), points (a), (b) and

(c)

Art. 23(1)

Art. 48(1) and (2)

Art. 23(2), 1st subparagraph,

introductory sentence and

points (a) and (b)

Art. 48(3)

Art. 23(2), 2nd subparagraph

Art.48(4)

Art. 23(3), 2nd subparagraph

Art. 48(5)

Art. 24

Art. 48(6)

Art. 28(1), 2nd subparagraph

Art. 49(1)

Art. 28(2)

Art. 49(2)

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Art. 28(3), 1st sentence

Art. 49(3)

Art. 29, 3rd subparagraph

Art. 49(4)

Art. 20, 1st subparagraph

Art. 8

Art. 21

Art. 43

Art. 21a, 1st subparagraph

Art. 44(1), points (a) to (f)

Art. 21a, 2nd subparagraph

Art. 44(2)

Art. 22

Art. 45(1) and (2)

Art. 26(1)

Art. 47(1), points (a), (b) and

(c)

Art. 26(2) and (3)

Art. 47(2) and (3)

Art. 6(1a)

Art. 56(1)

Art. 23a, 1st subparagraph

Art. 56(2)

Art. 8(2)

Art. 56(6)

Art. 23a, 3rd subparagraph

Art. 56(9)

Art. 25

Art. 61

Art. 70

Art. 50

Art. 71(1)

Art. 51(1), points (a) to (d)

Art. 71(2)

Art. 51(3)

Art. 71(3)

Art. 51(4)

Art. 71(4) and (5)

Art. 51(5) and (6)

Art. 72

Art. 52

Art. 73

Art. 53

Art. 74

Art. 54

Art. 74a

Art. 55

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Art. 11, 1st subparagraph,

introductory sentence

Art. 62(1)

Art. 11, 2nd subparagraph

Art. 62(2)

Art. 11, 4th subparagraph

Art. 62(3)

Art. 58

Art. 63(1)

Art. 63(2), 1st subparagraph, 1st

sentence

Art. 63(2)

Art. 58

Art. 63(4)

Art. 59(1), 1st subparagraph,

introductory sentence

Art. 64(1)

Art. 59(1), 3rd subparagraph

Art. 64(2)

Art. 59(3)

Art. 64(3)

Art. 54, introductory sentence

Art. 65(1)

Art. 54a

Art. 67

Art. 66

Art. 68(1), (2) and (3)

Art. 67

Art. 68(4)

Art. 56

Art. 70

Art. 56a

Art. 71

Art. 57

Art. 72

Art. 62

Art. 73

Art. 63(1), 1st and 2nd

subparagraphs

Art. 74(1) and (2)

Art. 63(2), 1st subparagraph, 2nd

sentence

Art. 74(3)

Art. 63(3), 2nd sentence

Art. 74(4)

Art. 63(3), 1st sentence

Art. 75, introductory sentence

and points (a) and (b)

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Art. 61

Art. 76

Art. 60

Art. 78

Art. 64

Art. 79

Art. 65

Art. 77

Art. 10(5)

Art. 81(2), point (d)

Art. 10(6)

Art. 85

Art. 27

Art. 37

Art. 28(1)

Art. 34(1) and (2), Art. 36(1)

and (2)

Art. 28(2)

Art. 36(5) and (6)

Art. 28(3)

Art. 34(5)

Art 28(4) and (5)

Art. 34(6) and (7), Art. 36(6)

and (8)

Art. 29(1), (2) and (3)

Art. 38(1), (2) and (3)

Art. 29(4), 1st sentence

Art. 38(4)

Art. 29(6)

Art. 38(5)

Art. 30(1)

Art. 39

Art. 30(2)

Art. 40

Art. 32(1), (2) and (3)

Art. 41(1), (2) and (3)

Art. 32(4), 1st subparagraph,

introductory sentence and points

(a) to (d)

Art. 41(4), 1st subparagraph,

introductory sentence and

points (a) to (d)

Art. 32(4), 2nd and 3rd

subparagraph

Art. 41(4), 2nd and 3rd

subparagraph

Art. 32(5)

Art. 41(5)

Art. 33

Art. 42

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Art. 81, 3rd subparagraph

Art. 56(3), 2nd subparagraph

Art 33

Art.59

Art. 35

Art. 60

Art. 34

Art. 42

Art. 36(1)

Art. 86(1)

Art. 36(2)

Art. 86(2)

Art. 36(3)

Art. 86(3)

Art. 36(5)

Art. 86(4)

Art. 22a, 1st subparagraph,

introductory sentence and points

(a) and (b)

Art. 87(1), 1st subparagraph,

introductory sentence and

points (a) and (b)

Art. 22a, 2nd subparagraph

Art. 87(1), 2nd subparagraph

Art. 22a(2) and (3)

Art. 87(2) and (3)

Art. 22b

Art. 88

Art. 22c

Art. 89

Art. 23(1), (2) and (3)

Art. 90(1), (2) and (3)

Art. 23(4), 1st subparagraph

Art. 90(4), 1st sentence

Art. 23(4), 2nd subparagraph

Art. 90(5)

Art. 23b(1)

Art. 92(2)

Art. 23b(2)

Art. 92(3), 1st and 2nd sentence

Art. 23b(2a)

Art. 92(4), introductory

sentence and points (a) and (b)

Art. 35

Art. 93

Art. 45(1)

Art. 94(1)

Art. 46(3)

Art. 94(3)

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Art. 46(4)

Art. 94(4)

Art. 46(5)

Art. 94(5)

Art. 31(1), 1st subparagraph

Art. 95(1), 1st subparagraph, 1st

sentence

Art. 95(1), 1st subparagraph,

2nd sentence

Art. 31(1), 2nd to 5th

subparagraph

Art. 95(1), 2nd to 5th

subparagraph

Art. 31(2), (3) and (4)

Art. 95(2), (3) and (4)

Art. 101

Art. 96

Art. 102, 1st subparagraph, points

(a) to (e)

Art. 97(1)

Art. 102, 2nd subparagraph

Art. 97(2)

Art. 103

Art. 98

Art. 104(1) and (2)

Art. 99(1), (2) and (3)

Art. 104(3), 1st subparagraph

Art. 99(4)

Art. 104(3), 2nd subparagraph

Art. 99(5)

Art. 104(4)

Art. 99(6)

Art. 104a

Art. 100

Art. 105

Art. 101

Art. 106

Art. 102(1) , introductory

sentence and points (a) to (c),

(e)

Art. 107l

Art. 103

Art. 106a

Art. 104

Art. 107

Art. 105(1) to (5)

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Art. 107a(1), 1st subparagraph,

1st sentence

Article 106(1), 1st

subparagraph, 1st sentence

Art. 107a(1), 1st subparagraph,

2nd sentence

Article 106(1), 1st

subparagraph, 3rd sentence

Art. 107a(1), 2nd subparagraph

Art. 106(1), 2nd subparagraph

Art. 107a(2) to (6)

Article 106(2) to (6)

Art. 107b(1), 1st subparagraph

Art. 107(1), 1st subparagraph

Art. 107b(1), 2nd and 3rd

subparagraph

Art. 107(2)

Art. 107b(2) and (3)

Art. 107(3) and (4)

Art. 107c

Art. 108

Art. 107d

Art. 109

Art. 107e

Art. 110

Art. 107f

Art. 111

Art. 107g

Art. 112

Art. 107h

Art. 113

Art. 107i

Art. 114

Art. 107j

Art. 115

Art. 107k

Art. 116

Art. 107m

Art. 117

Art. 107n

Art. 118

Art. 107o

Art. 119

Art. 107p

Art. 120

Art. 107q

Art. 121

Art. 108

Art. 122

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Art. 108a

Art. 123

Art. 108b

Art. 124

Art. 13

Art. 125

Art. 14

Art. 126

Art. 15

Art. 127

Art. 39

Art. 128

Art. 68

Art. 129

Art. 69

Art. 130

Art. 100

Art. 131

Art. 124

Art. 132

Art. 16(1) and (2)

Art. 133

Art. 16(3), 53, 85, 119

Art. 133(3)

Art. 16a

Art. 134

Art. 16b

Art. 135

Art. 16c

Art. 136

Art. 16d

Art. 137

Art. 16e

Art. 138

Art. 16f

Art. 139

Art. 16g

Art. 140

Art. 16h(1)

Art. 141(1)

Art. 16h(2)

Art. 141(2), 1st and 2nd

subparagraph

Art. 16h(2), 5th subparagraph

Art. 141(2), 3rd subparagraph

Art. 16h(3) and (4)

Art. 141(3) and (4)

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Art. 40(1)

Art. 142(1)

Art. 40(2), 1st subparagraph

Art. 142(2)

Art. 40(2), 2nd subparagraph

Art. 142(3), introductory

sentence and point (a)

Art. 40(3)

Art. 142(4)

Art. 40(4)

Art. 142(5)

Art. 41, 1st subparagraph

Art. 143(1), introductory

sentence and points (a), (b) and

(c)

Art. 41, 2nd subparagraph

Art. 143(2)

Art. 42

Art. 144(1), 1st subparagraph,

144(2) and (3)

Art. 43

Art 144(1), 2nd subparagraph

Art. 44

Art. 145

Art. 45

Art. 146

Art. 46

Art. 147(1) and (2)

Art. 47a

Art. 149

Art. 52b(1)

Art. 150(1)

Art. 118b

Art. 150(2)

Art. 52b(2)

Art. 150(3)

Art. 48(1) and (2)

Art. 151(1) and (2)

Art. 49(1)

Art. 152(1)

Art. 51

Art. 153(1), (2) and (3)

Art. 52

Art. 154

Art. 52a

Art. 157

Art. 47, 1 to 4th subparagraph

Art. 160

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Art. 47, 5th subparagraph

Art. 161

Art. 127

Art. 155

Art. 46a

Art. 156

Art. 52a

Art. 157

Art. 46b(1), (2) and (3)

Art. 158(1), (2) and (3)

Art. 46b(4)

Art. 158(4)

Art. 111b

Art. 159

Art. 76

Art. 162

Art. 77

Art. 163

Art. 78

Art. 165(1), 2nd sentence

Art. 79

Art. 164

Art. 80

Art. 166(1) to (4)

Art. 81

Art. 167

Art. 82

Art. 168

Art. 83

Art. 169

Art. 85a

Art. 170

Art. 85b(1)

Art. 171(1)

Art. 85b(2), 1st and 3rd

subparagraph

Art. 171(2)

Art. 85b(3) and(4)

Art. 171(3) and (4)

Art. 85c(1) and (2)

Art. 172(1) and (2)

Art. 85c(6)

Art. 172(3)

Art. 85c(3)

Art. 173(1) and (2)

Art. 85c(4)

Art. 174(1)

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Art. 85c(5)

Art. 174(2)

Art. 85d

Art. 174(3)

Art. 86

Art. 175

Art. 87

Art. 176(1), (2) and (3)

Art. 88

Art. 177

Art. 89

Art. 178

Art. 90

Art. 179

Art. 91

Art. 180

Art. 92

Art. 181

Art. 93

Art. 182

Art. 94

Art. 183

Art. 95

Art. 184

Art. 96(1)

Art. 185(1)

Art. 96(2)

Art. 185(3)

Art. 97

Art. 186

Art. 98

Art. 187

Art. 111(1)

Art. 188(1), (2) and (6)

Art. 111(1a)

Art. 188(3), point (a)

Art. 111(1b), 1st subparagraph

Art. 188(3), point (b)

Art. 111(1b), 2nd subparagraphs,

points (a) and (b)

Art. 188(5), points (b), (d) and

(f)

Art. 111(1c)

Art. 188(6)

Art. 111(1d)

Art. 188(5), point (g)

Art. 111(1g)

Art. 188(7)

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Art. 111(1h)

Art. 188(8)

Art. 111(3), first subparagraph

Art. 188(9)

Art. 111(3), 2nd subparagraph

Art. 188(10)

Art. 111(3), 3rd subparagraph

Art. 188(11)

Art. 111(4)

Art. 188(12)

Art. 111(5), 1st subparagraph

Art. 188(13)

Art. 111(6)

Art. 188(15)

Art. 111(7)

Art. 188(16)

Art. 111(8)

Art. 188(17)

Art. 111a, 1st subparagraph

Art. 190(1)

Art. 111a, 2nd subparagraph

Art. 190(2)

Art. 112

Art. 191

Art. 113

Art. 192

Art. 114

Art. 193

Art. 115

Art. 194

Art. 116, 1st subparagraph

Art. 195(1)

Art. 116, 2nd and 3rd

subparagraph

Art. 195(3) and (4)

Art. 118(1)

Art. 195(5)

Art. 117(1)

Art. 196(1), introductory

sentence and points (a) to (e)

Art. 117(2) and (3)

Art. 196(2) and (3)

Art. 117a(1) to (3)

Art. 197

Art. 118(2)

Art. 198

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Art. 126

Art. 199

Art. 118a

Art. 206

Art. 118(c)

Art. 201(2)

Art. 122

Art. 202

Art. 123

Art. 203

Art. 125

Art. 204

Art. 126a(1) to (4)

Art. 205

Art. 126b

Art. 208

Art. 127b

Art. 207

Art. 5a

Art. 209(1)

Art. 8(2a), (2b), 1st subparagraph

Art. 209(2), 1st subparagraph

Art. 8(2b), 2nd subparagraph

Art. 209(2), 2nd subparagraph

Art. 18a(1) and (2)

Art. 209(3) and (4)

Art. 20, 2nd subparagraph

Art. 209(5)

Art. 40(1a), 1st subparagraph

Art. 209(6)

Art. 40(3a)

Art. 209(7)

Art. 48(3)

Art. 209(8)

Art. 104(3), 3rd subparagraph

Art. 209(9)

Art. 127d(1)

Art. 209(10)

Art. 111c

Art. 210

Art. 8(2b)

Art. 211(1)

Art. 20, 2nd subparagraph

Art. 211(2)

Art. 40(1a)

Art. 211(3)

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Art. 40(3a)

Art. 211(4)

Art. 126c

211(5)

Art. 127d

Art. 211(9)

Art. 127c

Art. 212

Art. 120

Art. 213

Art. 121(1)

Art. 214(1)

Art. 121(2), 1st subparagraph

Art. 214(2)

Art. 121(3), 1st subparagraph

Art. 214(3)

Art. 121(4)

Art. 214(4)

Art. 121a

Art. 215

Art. 8(3), points (a) to (c)

Annex I, points (1), (2) and (3)

Art. 8(3), points (d) to (i)

Annex I, points (6) to (12)

Art. 8(3), points (ia) to (m)

Annex I, points (14) to (20)

Art. 9

Annex I, point (22)

Annex I

Annex II

Art. 49(2)

Annex IV, point (1)

Art. 49(2)

Annex IV, point (4)

Art, 49(3), 1st subparagraph

Annex IV, point (5)

Art. 50(1)

Annex IV, point (6)

Art. 50(2), 1st subparagraph

Annex IV, point (7)

Art. 54

Art. 65; Annex V

Art. 11

Annex VI

Art. 59

Annex VII, points (1) to (7)